BCD tricyclic ergoline part-structure analogues

ABSTRACT

7- or 8-Substituted, partially hydrogenated pyrazolo[3,4-g]quinoline, thiazolo[4,5-g]quinoline, oxazolo[4,5-g]quinoline, and pyrrolo[3,4-g]quinoline derivatives, and 8- or 9-substituted, partially hydrogenated pyrido[2,3-g]quinazoline derivatives are D-2 dopamine agonists. 6-Oxo-1-substituted-octahydroquinolines and 6-oxo-1-substituted-decahydroquinolines which are additionally substituted in the 3- or 4-position are intermediates useful in preparation of the dopamine agonists. Acetals of 4,6-dioxo-1-substituted-decahydroquinoline 3-carboxylic acid esters enable synthesis of the foregoing compounds.

This application is a division of application Ser. No. 07/311,904, filedFeb. 16, 1989, now U.S. Pat. No. 4,977,160, which is a division ofapplication Ser. No. 06/874,741, filed Jun. 16, 1986, now U.S. Pat. No.4,826,986.

This invention relates to ergoline analogues, and more particularly toBCD tricyclic ergoline part-structure analogues, to intermediates usedto prepare such analogues, and to use of such analogues as dopamineagonists.

BACKGROUND OF THE INVENTION

The ergoline ring is a tetracycle having the following structure##STR1##

Certain substituted ergolines are known to be D-2 dopamine agonistshaving the ability to inhibit the secretion of prolactin and to affectfavorably the symptoms of Parkinson's Syndrome. For example, in theforegoing structure when R is n-propyl, R' is methylthiomethyl, and R"is H, the substituted ergoline has been given the generic namepergolide. It is disclosed in U.S. Pat. No. 4,166,182. Pergolide is onclinical trial for the treatment of Parkinsonism and for certainconditions in which there is an excess of circulating prolactin, i.e.,galactorrhea and inappropriate lactation. Another such ergoline drug isα-bromoergocryptine, named generically as bromocriptine. It is disclosedin U.S. Pat. Nos. 3,752,814 and 3,752,888. For bromocriptine R" is Br, Ris methyl and R' is the ergocryptine side chain. While both ergolinesare D-2 dopamine agonists, bromocriptine, and to a lesser extentpergolide, also have some alpha blocking activity.

BCD tricyclic ergoline part-structure compounds having the followingformula ##STR2## wherein R is lower alkyl, have been synthesized, andare disclosed in Bach et al, J. Med. Chem., 23, 481 (1980) and U.S. Pat.No. 4,235,909. These products were prepared a racemates composed of theenantiomer illustrated above together with the mirror image thereof. Inboth enantiomers the R' substituent is equatorial. These compounds showactivity in prolactin inhibition and rat-turning behavior tests,indicating that D-2 dopamine agonist activity is present. Relatedcompounds in which the C-1 carbon is replaced by nitrogen to form apyrazole ring are also disclosed by Bach et al. in J. Med. Chem., 23,481 (1980) and in U.S. Pat. No. 4,198,415. These pyrazoloquinolines arealso D-2 dopamine agonists, and they too were prepared only as theracemate wherein the R' substituent of each enantiomer is equatorial.

SUMMARY OF THE INVENTION

This invention provides BCD tricyclic ergoline part-structur analoguesof the formula (1) ##STR3## wherein: the C and D rings are trans fused;

R¹ is (C₁ -C₃) alkyl, allyl, or cyclopropylmethyl;

R² is hydrogen, CH₂ OH, CH₂ OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂R⁶, or CONR⁷ R⁸, where R⁶ is hydrogen, (C₁ -C₄)alkyl or benzyl, and R⁷and R⁸ are independently selected from hydrogen, (C₁ -C₄)alkyl, phenyl,benzyl, and phenethyl;

R³ is hydrogen, OH, NH₂, NHCOR⁹ or NHSO₂ NR⁹ R¹⁰, where R⁹ and R¹⁰ areindependently selected from hydrogen, (C₁ -C₄)alkyl, and phenyl, or R³and R⁵ combine to form ═O or ═NOH;

R⁴ and R⁵ are both hydrogen, or combine to form a carbon-carbon bond,except that R⁴ is hydrogen when R⁵ combines with R³ to form ═O or ═NOH;

provided that one of R² and R³ is hydrogen and the other is nothydrogen, and further provided that R² is hydrogen unIess R⁴ and R⁵combine to form a carbon-carbon bond; and ##STR4## represents ##STR5##where R^(10a) is hydrogen or (C₁ -C₃)alkyl, R¹¹ and R¹² areindependently hydrogen or (C₁ -C₃)alkyl, and R¹³ is hydrogen, NR¹¹ R¹²,or (C₁ -C₃)alkyl, and pharmaceutically acceptable salts thereof.

The invention also provides BCD tricyclic ergoline part-structureanalogues having the following structures (2a) and (2b) ##STR6## whereR¹ is (C₁ -C₃) alkyl, allyl, or cyclopropylmethyl;

R² is CH₂ OH, CH₂ OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂ R⁶, orCONR⁷ R⁸, where R⁶ is hydrogen, (C₁ -C₄)alkyl or benzyl, and R⁷ and R⁸are independently selected from hydrogen, (C₁ -C₄)alkyl, phenyl, benzyl,and phenethyl; and

B is as defined for formula (1), and pharmaceutically acceptable acidaddition salts thereof. Compounds of formula (2a) and (2b) areenantiomers. When "compounds of formula (2)" are referred tohereinafter, the racemate is intended.

The invention also provides BCD tricyclic ergoline part-structureanalogues having the following structures (3a) and (3b ##STR7## whereinR¹ is (C₁ -C₃) alkyl, allyl, or cyclopropylmethyl; and

R² is CH₂ OH, CH₂ OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂ R⁶, orCONR⁷ R⁸, where R⁶ is hydrogen, (C₁ -C₄)alkyl or benzyl, and R⁷ and R⁸are independently selected from hydrogen, (C₁ -C₄)alkyl, phenyl, benzyl,and phenethyl; and ##STR8## wherein R¹¹, R¹², and R¹³ are as defied informula (1), and pharmaceutically acceptable acid addition saltsthereof. Compounds of formulas (3a) and (3b) are enantiomers, andreference to "compounds of formula (3)" means the racemate.

The pharmaceutically-acceptable acid addition salts of compounds offormulas (1), (2) and (3) include salts derived from inorganic acidssuch as: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid,hydrobromic acid, hydriodic acid, nitrous acid, phosphorous acid and thelike, as well as salts derived from nontoxic organic acids such asaliphatic mono and dicarboxylic acids, phenyl-substituted alkanoicacids, hydroxy alkanoic and alkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids. Such pharmaceutically-acceptable salts thusinclude sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate,phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, benzenesulfonate, toluenesulfonate,chlorobenzenesulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycollate, malate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like salts.

The synthetic procedures discussed herein produce compounds of formulas(1), (2), and (3) as racemates.

In the case of compounds of formula (1) wherein R² is other thanhydrogen and R⁴ and R⁵ combine to form a carbon-carbon bond, theracemates produced are composed of enantiomers having the structures##STR9## In naming these products herein, the racemate is not explicitlyindicated, but it is to be understood that such products are racemates.Accordingly, products of this type are named as:

a) trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo-[3,4-g]quinolines,

b) trans-4,4a,5,6,8a,9-hexahydro-1H-pyrazolo-[3,4-g]quinolines,

c) trans-5,5a,6,7,9a,10-hexahydropyrido -[2,3-g]quinazolines,

d) trans-4,4a,5,6,8a,g-hexahydrothiazolo -[4,5-g]quinolines,

e) trans-4,4a,5,6,8a,9-hexahydrooxazolo -[4,5-g]quinolines, and

f) trans-4,4a,5,6,8a,9-hexahydropyrrolo -[3,4-g]quinolines.

The 4,4a,5,6,8a,9-hexahydro-2H-pyrazolo3,4-g]-quinolines (a) and thecorresponding 4,4a,5,6,8a,9-hexahydro-1H-pyrazolo[3,4-g]quinolines (b)of formula (1) wherein R^(10a) is hydrogen represent tautomeric pairs,and the tautomers are in dynamic equilibrium. It will therefore beunderstood that when one of the tautomers is referred to, the other isalso implied.

In the case of compounds of formula (I) wherein R³ combines with R⁵ toform ═O or ═NOH, each compound is again produced as a racemate. Again,this is not explicitly indicated in naming these compounds, but is to beunderstood. These compounds are named as:

a) trans-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines,

b) trans-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines,

c) trans-5,5a,6,7,8,9,9a,10-octahydropyrido -[2,3-g]quinazolines,

d) trans-4,4a,5,6,7,8,8a,9-octahydrothiazolo -[4,5-g]quinolines,

e) trans-4,4a,5,6,7,8,8a,9-octahydrooxazolo -[4,5-g]quinolines, and

f) trans-4,4a,5,6,7,8,8a,9-octahydropyrrolo -[3,4-g]quinolines.

Again, the 4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines andthe corresponding4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines of formulas (1)and (2) wherein R^(10a) is hydrogen represent tautomers that exist inequilibrium with each other.

The compounds of formula (1) wherein R³ is OH, NH₂, NHCOR⁹ or NHSO₂ NR⁹R¹⁰ have an additional chiral center at the carbon atom to which theR^(10a) substituent is attached. The synthetic procedures disclosedherein allow production of two diastereomers: one composed ofenantiomers (5a) and (5b), wherein the R³ substituent is axial, and theother composed of enantiomers (6a) and (6b), wherein the R³ substituentis equatorial. ##STR10## The racemates composed of enantiomers (5a) and(5b) are named herein by attaching the prefix rac to the name ofenantiomer (5a). Enantiomer (5a) is indicated by the prefix (4aβ, 8β,8aα), or (5aβ, 9β, 9aα) in the case of quinazolines. Accordingly,products of this type are named as:

a) rac-(4aβ, 8β, 8aα)-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines,

b) rac-(4aβ, 8β, 8aα)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines,

c) rac-(5aβ, 9β, 9aα)-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolines,

d) rac-(4aβ,8β,8aα)-4,4a,5,6,7,8,8a,g-octahydrothiazolo4,5-g]quinolines,

e) rac-(4aβ,8β,8aα)-4,4a,5,6,7,8,8a,9-octahydrooxazolo[4,5-g]quinolines,and

f) rac-(4aβ,8β,8aα)-4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4-g]quinolines.

The racemates composed of enantiomers (6a) and (6b) are named herein byprefixing rac to the name of enantiomer (6a). Enantiomer (6a) isindicated by the prefix (4aβ, 8α, 8aα) or (5aβ, 9α, 9aα). Accordingly,products of this type are named as:

a)rac-(4aβ,8α,8aα)-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines,

b)rac-(4aβ,8α,8aα)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines,

c)rac-(5aβ,9α,9aα)-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolines,

d) rac-(4aβ,8α,8aα)-4,4a,5,6,7,8,8a,9-octahydrothiazolo4,5-g]quinolins,

e) rac-(4aβ,8α,8aα)-4,4a,5,6,7,8,8a,9-octahydrooxazolo[4,5-g]quinolines,and

f) rac-(4aβ,8α,8aα)-4,4a,5,6,7,8,8a,9-octahydropyrrolo3,4-g]quinolines.

Compounds having structures (2a)and (2b) are enantiomers, and areprepared as racemic mixtures by the methods discussed hereinafter. Thecompounds are named as:

a)rac-(4aβ,7α,8aα)-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolines,

b)rac-(4aβ,7α,8aα)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]quinolines,

c)rac-(5aβ,8α,9aα)-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolines,

d)rac-(4aβ,7α,8aα)-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolines,

e) rac-(4aβ,7α,8aα)-4,4a,5,6,7,8,8a,9-octahydrooxazolo[4,5-g]quinolines,and

f) rac-(4aβ,7α,8aα)-4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4-g]quinolines.

In each of the enantiomers the substituent R² has the axial orientation.U.S. Pat. No. 4,198,415 describes compounds having the same formula, butthe racemic mixtures produced by the procedures described in that patentare ones wherein the substituent R² has the equatorial orientation.

Compounds having structures (3a) and (3b) are likewise enantiomers, andthey too are prepared as racemic mixtures in the methods discussedhereinafter. These compounds are named as:

a)rac-(5aβ,8β,9aα)-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolines,

b)rac-(4aβ,7β,8aα)-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinolines,

c) rac-(4aβ,7β,8aα)-4,4a,5,6,7,8,8a,9-octahydrooxazolo[4,5-g]quinolines.

Preparation of pyrazolo[3,4-g]quinolines

The pyrazolo[3,4-g]quinoline derivatives of formulas (1) and (2) can beprepared by reacting a 7-dimethylaminomethylene-6-oxo-trans-quinolinederivative of formula (7a) or (7b) with a compound of formula NH₂NHR^(10a), wherein R^(10a) is hydrogen or (C₁ -C₃)alkyl. The preparationof pyrazolo[3,4-g]quinoline derivatives of formula (1), for example, isillustrated in Reaction Scheme I: ##STR11## wherein R¹, R², R³, R⁴ andR⁵ are as previously defined, and R^(10a) is hydrogen or (C₁ -C₃)alkyl.The pyrazolo[3,4-g]quinolines of formulas (2) can be prepared using thesame procedure with starting materials of formula (7b). ##STR12##Suitable solvents for this reaction are polar organic solvents, such asC₁ -C₄ alkanols, DMSO, DMF, and acetonitrile. The reaction is run atroom temperature to reflux, preferably in an inert atmosphere, such asnitrogen. In each of the structures in Reaction Scheme I, as well as inthe following Reaction Schemes, it should be understood that thequinoline ring system is trans fused. Preparation ofpyrazolo3,4-g]quinolines of formula (1) and (2) by the procedure ofReaction Scheme 1 is exemplified hereinafter in Examples 7, 16, 24, 26,and 28.

The pyrazolo[3,4-g]quinoline derivatives of formula (1) and (2) can alsobe prepared by formylating a 6-oxo-trans-quinoline derivative of formula(12a) or (12b): ##STR13## wherein R¹, R², R³ and R⁴ are as previouslydefined, with a (C₁ -C₆)alkyl formate, preferably ethyl formate, in thepresence of base to yield the corresponding7-formyl-6-oxo-trans-quinoline derivative. The base can be, for example,an alkali metal alkoxide or hydride, such as potassium t-butoxide orsodium hydride, or sodium ethoxide. The reaction can be carried outusing a lower alkanol or similar polar anhydrous organic compound, suchas THF, diethyl ether, or DMSO as solvent. THF is a preferred solvent.Although the temperature of the reaction is not critical, a range ofabout -20° C. to reflux may be used, with 0° C. to room temperaturebeing preferred. The 7-formyl-6-oxo-trans-quinoline derivative thusprepared is reacted with hydrazine or a (C₁ -C₃) alkyl substitutedhydrazine to give the products of formulas (1) and (2). This step can becarried out without isolating the 7-formyl-6-oxo-trans-quinolineintermediate. The reaction can be run at a temperature from about 0° C.to reflux, with room temperature being preferred. This process isexemplified in Examples 1, 8, 12, 18, 20, and 23.

Preparation of pyrido[2,3-g]quinazolines

The pyrido[2,3-g]quinazoline derivatives of formulas (1), (2) and (3)are prepared by reacting a7-dimethylaminomethylene-6-oxo-trans-quinoline derivative of formula(7a) or (7b), shown above, or (7c), ##STR14## wherein R¹ and R² are asdefined previously, with quanidine or a guanidine derivative of##STR15## wherein R¹¹ and R¹² are independently hydrogen or (C₁-C₃)alkyl, as illustrated for preparation of compounds of formula (1) inReaction Scheme II: ##STR16## The pyrido[2,3-g]quinazolines of formulas(2) and (3) are prepared using the same procedure and starting materialsof formulas (7b) and (7c) respectively. Suitable solvents are polarorganic solvents, such as (C₁ -C₄) alkanols, DMSO, DMF, andacetonitrile. The reaction is run at room temperature to reflux,preferably in an inert atmosphere, such as nitrogen. Preparation ofpyrido[3,4-g]quinazolines of formulas (1), (2) and (3) is exemplified inExamples 2, 6, 10, 11, 14, 15, 17, 25, 27, 29, and 33-35.

Preparation of pyrrolo[3,4-g]quinolines

The pyrrolo[3,4-g]quinoline derivatives of formula (1) and (2) areprepared by reacting a 7-dimethylaminomethylene-6-oxo-trans-quinolinederivative of formula (7a) or (7b) with potassium glycinate, followed bytreatment of the thus formed intermediate product with acetic anhydride.This yields a 2-acetylpyrrolo[3,4-g]quinoline compound. The acetyl groupis removed by basic hydrolysis, for example using sodium ethoxide inethanol. Preparation of the pyrrolo3,4-g]-quinolines of formula (1) isillustrated in Reaction Scheme III: ##STR17## Thepyrrolo[3,4-g]quinolines of formula (2) are prepared using the sameprocedure and starting materials of formula (7b).

Preparation of 7-dimethylaminomethylene-6-oxo-trans-quinolineintermediates

The 7-dimethylaminomethylene-6-oxo-trans-quinoline derivatives offormulas (7a), (7b), and (7c), which are used in preparation of thepyrazolo[3,4-g] -quinolines, the pyrido[2,3-g]quinazolines, and thepyrrolo[3,4-g]quinolines of this invention can be prepared by reacting a6-oxo-trans-quinoline derivative of formula (12a) or (12b), shown above,or (12c) ##STR18## wherein R¹ and R² are previously defined, with adimethylformamide acetal or, preferably, tris(dimethylamino)methane, asillustrated for compounds of formula (1) in Reaction Scheme IV:##STR19## wherein R¹, R², R³, R⁴, and R⁵ are as previously defined and Xis --N(CH₃)₂ or OR¹⁴ and R¹⁴ is (C₁ -C₈)alkyl, (C₅ -C₆)cycloalkyl, (C₃-C₄)alkenyl, and (C₃ -C₄)alkynyl.

The 7-dimethylaminomethylene-6-oxo-trans-quinoline derivatives offormulas (7a), (7b), and (7c) are preferably formed by reacting theintermediates of formulas (12a), (12b), and (12c), respectively, withtris(dimethylamino)methane in a nonpolar organic solvent such astoluene. Preparation of compounds of formulas (7a), (7b) and (7c) usingthis procedure is exemplified as the first step in Examples 2, 6, 7, 10,14, 16, 17, 24, 26, and 28. It should be understood that the compoundsof formulas (7a), (7b), and (7c) are prepared as racemates, althoughonly one enantiomer is illustrated in the foregoing structures. The sameis true of the intermediates of formulas (12a), (12b) and (12c).

Preparation of thiazolo[4,5-g]quinolines

The thiazolo[4,5-g]quinoline derivatives of formulas (1), (2) and (3)where R¹³ is NR¹¹ R¹² or (C₁ -C₃)alkyl are prepared by reacting a7-bromo-6-oxo-trans-quinoline derivative of formula (13a), (13b) or(13c) ##STR20## wherein R¹, R², R³, R⁴, and R⁵ are as previouslydefined, with a thiourea or thioamide of ##STR21## wherein R^(13a) is(C₁ -C₃)alkyl or NR¹¹ R¹² and R¹¹ and R¹² are as previously defined.This reaction is illustrated for compounds of formula (1) in ReactionScheme V: ##STR22## The process of Reaction Scheme V is exemplified inExamples 3, 30, and 36. Thiazolo[4,5-g]quinoline derivatives of Formulas(1), (2), and (3) wherein R¹³ is hydrogen are prepared by diazotizingthe primary amine group of compounds of formulas (1), (2) and (3)wherein R¹³ is NH₂, and treating the diazonium salt with hypophosphorousacid. This process is exemplified in Examples 4, 32, and 38.

Preparation of oxazolo[4,5-g]quinolines

The oxazolo[4,5-g]quinoline derivatives of formulas (1), (2) and (3) areprepared by reacting a 7-bromo-6-oxo-trans-quinoline derivative offormula (13a), (13b) or 13c) with urea, as illustrated for compounds offormula (1) in Reaction Scheme VI: ##STR23## This reaction can beconducted at temperatures from 40° to 100° C. Preferred solvents areorganic polar solvents such as C₁ -C₃ alkanols. Theoxozolo[4,5-g]quinolines of formulas (2) and (3) are prepared using thesame procedure and starting materials of formulas (13b) and (13c)respectively.

Preparation of 7-bromo-6-oxo-trans-quinoline intermediates

The 7-bromo-6-oxo-trans-quinoline derivatives of formula (13) that areused in preparation of the thiazolo[4,5-g]quinoline derivatives and theoxazolo -[4,5-g]quinoline derivatives of this invention can be preparedby brominating the corresponding 6-oxo-trans -quinoline derivatives offormula (12), using, for example, hydrogen bromide and bromine inglacial acetic acid, permissibly in the presence of UV light. Thisprocess is exemplified in the first step of Example 3.

Substituents R¹, R², R³, R⁴ and R⁵

Compounds of formulas (1), (2), and (3) wherein R² is CO₂ R⁶ areprepared from intermediates of

5 formulas (7) and (13) wherein R² is CO₂ R⁶ using the proceduresdescribed above, as exemplified in Examples 3, 30, and 36. Compounds offormula (1), (2), and (3) where R² is CO₂ H can be prepared byhydrolyzing compounds of formulas (1), (2), and (3) wherein R² is CO₂R^(6a) and R^(6a) is (C₁ -C₄)alkyl or benzyl.

Compounds of formulas (1), (2), and (3) wherein R² is CH₂ OH arepreferably prepared from intermediates of formulas (7) and (13) whereinR² is CH₂ OH, as exemplified in Examples 1, 2, 12-15, 23-25, 32-33 and38. Alternatively, compounds of formulas (1), (2), and (3) can beprepared by reducing the corresponding compound of formula (1), (2) or(3) wherein R² is CO₂ R⁶, as exemplified in Examples 5, 22, 31, and 37.

Compounds of formulas (1), (2), and (3) wherein R² is CH₂ OCH₃ arepreferably prepared from intermediates of formulas (7) and (13) whereinR² is CH₂ OCH₃, as exemplified in Examples 6, 7, 26, 27, and 34.

Compounds of formulas (1), (2), and (3) wherein R² is --CH₂ SCH₃ can beprepared by converting compounds of formulas (1), (2), and (3) whereinR² is --CH₂ OH to the corresponding chloride or bromide, and thendisplacing the halide with methyl mercaptide. Preferably, compounds offormulas (1), (2), and (3) wherein R² is --CH₂ SCH₃ are prepared fromintermediates of formulas (7) and (13) where R² is --CH₂ SCH₃, asexemplified in Examples 8, 10, 28, 29, and 35.

Preparation of compounds of formulas (1), (2), and (3) wherein R² is CH₂SOCH₃ can be prepared by oxidizing the corresponding compound of formula(1), (2) or (3) wherein R² is CH₂ SCH₃, as exemplified in Examples 9 and11.

Compounds of formulas (1), (2) and (3) wherein R² is CH₂ SO₂ CH₃ can beprepared from the corresponding compounds wherein R² is CH₂ SCH₃ or CH₂SOCH₃ using conventional oxidation procedures.

Compounds of formulas (1), (2) and (3) wherein R² is CONR⁷ R⁸ can beprepared from the corresponding esters using conventional procedures.

Compounds of formula (1) wherein R³ is hydroxy are preferably preparedfrom the corresponding rac-(4α,4aα,8aβ)-4-hydroxy-decahydroquinolin-6-ones andrac-(4β,4aα,8aβ)-4-hydroxy-decahydroquinolin -6-ones of formula (12a)wherein R³ is hydroxy using the procedures illustrated in the precedingReaction Schemes, as exemplified in Examples 12-15.

Compounds of formula (1) wherein R³ is NHCOR⁹ can be prepared from thecorresponding rac-(4α,4aα,8aβ) -4-acylaminodecahydroquinolin-6-ones andrac-(4β,4aα, 8aβ)-4-acylaminodecahydroquinolin-6-ones of formula (12a)using the procedures illustrated in the preceding Reaction Schemes, asexemplified in Examples 18 and 20.

Compounds of formula (1) wherein R³ is NHSO₂ NR⁹ R¹⁰ can be obtainedfrom the corresponding rac-(4α,4aα,8aβ)-4-(NHSO₂ NR⁹R¹⁰)-decahydroquinolin-6-ones and rac-(4β,4aα, 8aβ)-4-(NHSO₂ NR⁹R¹⁰)decahydroquinolin -6-ones of formula (12a) using the proceduresillustrated in the foregoing Reaction Schemes, as exemplified inExamples 16 and 17.

Compounds of formula (1) wherein R³ is NH₂ can be prepared by hydrolysisof the corresponding compound of formula (1) wherein R³ is NCOR⁹, asexemplified in Examples 19 and 21.

Compounds of formula (1) wherein R³ and R⁵ combine to form oxo areprepared by oxidizing the corresponding compound of formula (1) whereinR³ is hydroxy, using conventional oxidation procedures, such as theJones, Swern, Moffat, or Corey-Kim procedures.

Oximes of formula (1) wherein R³ and R⁵ combine to form hydroxyimino canbe prepared by reacting the corresponding compound of formula (1)wherein R³ and R⁵ combine to form oxo with hydroxylamine or a saltthereof.

Compounds of formula (3) wherein R¹ is allyl are preferably preparedfrom corresponding compounds of formula (3) wherein R¹ is methyl orbenzyl. In this procedure, the methyl or benzyl group is removed bytreatment with cyanogen bromide to give an intermediate wherein R¹ isCN. Reductive (Zn and acetic acid) cleavage of the N-cyano compoundgives the secondary amine, which is then alkylated with, for example,allyl bromide or allyl chloride.

ADDITIONAL INTERMEDIATES

The 6-oxo-trans-quinoline derivatives of formula (12), which are used toprepare the intermediates of formulas (7) and (13), also form a part ofthis invention. Compounds of formula (12a) wherein R⁴ and R⁵ combine toform a carbon-carbon bond are prepared as racemates composed ofenantiomers having structures ##STR24## Racemic mixtures composed ofenantiomer (16a) and (16b) are named as6-oxo-trans-1,2,4a,5,6.7,,8,8a-octahydroquinolines, it being understoodthat the racemic mixture is intended.

Compounds of formula (12a) wherein R³ is OH, NH₂, NHCOR⁹ or NHSO₂ NR⁹R¹⁰, like the corresponding final products of formulas (5) and (6), havean additional chiral center at the carbon atom to which the R³substituent is attached. Accordingly, two diastereomers are possible:one composed of enantiomers (17a) and (17b), wherein the Rz substituentis axial, and the other composed of enantiomers (18a) and (18b) whereinthe R³ substituent is equatorial. ##STR25## The racemates composed ofenantiomers (17a) and (17b) are named herein asRac-(4β,4aα,8aβ)-6-oxodecahydroquinolines. The racemates composed ofenantiomers (18a) and (18b) are named asrac-(4α,4aα,8aβ)-6-oxodecahydroquinolines.

Compounds of formula (12b) are prepared as racemic mixtures, composed ofenantiomers (19a) and (19b) ##STR26## These racemates are named hereinas rac-(3α,4aα,8aβ)-6-oxodecahydroquinolines.

Compounds of formula (12c) are prepared as racemic mixtures composed ofenantiomers (20a) and (20b) ##STR27## These racemates are named hereinas rac-(3β,4aα,8aβ)-6-oxodecahydroquinolines.

Methods of preparing compounds of formula (16) are illustrated inReaction Scheme VII. In the first step the 4-oxo group of a compound offormula (21), wherein R¹ and R⁶ are as previously defined and R¹⁵ andR¹⁶ are individually (C₁ -C₃)alkyl or combine to form --(CH₂)_(n) --where n is 2-4, is reduced using, for example, sodium borohydride, toproduce the corresponding alcohol of formula (22). In the second stepthe alcohol is converted to the corresponding mesylate of formula (23).Elimination of methanesulfonic acid from the mesylate produces theα,β-unsaturated ester of formula (24). These three steps are illustratedhereinafter in Preparation 1. ##STR28##

Acid hydrolysis of the α,β-unsaturated ester of formula (24), usinghydrochloric acid for example, produces the6-oxo-1-substituted-trans-1,2,4a,5,6,7,8,8a-octahydroquinoline offormula (16-I), which is useful in preparing compounds of formula (4)wherein R² is CO₂ R⁶. The acid hydrolysis step is exemplifiedhereinafter in Preparation 3.

Reduction of the α,β-unsaturated ester of formula (24) usingdiisobutylaluminum hydride produces the corresponding allylic alcohol offormula (25). Acid hydrolysis of the acetal portion of the compound offormula (25) produces the3-(6-oxo-1-substituted-trans-1,2,4a,5,6,7,8,8a-octahydroquinoline)methanolof formula (16-II), which is useful in preparing compounds of formula(4) wherein R² is CH₂ OH. Preparation 2 exemplifies conversion of acompound of formula (24) to one of formula (16-II).

Deprotonation of the allylic alcohol of formula (25) using a strong basesuch as sodium amide, followed by treatment with methyl iodide producesthe3-methoxymethyl-1-substituted-trans-1,2,4a,5,6,7,8,8a-octahydro-quinoline-6-oneacetal of formula (26), which is hydrolyzed with hydrochloric acid toprovide the ketone of formula (16-III). These steps are exemplified inPreparation 4.

The allylic alcohol of formula (25) is chlorinated, preferably usingtriphenylphosphinedichloride, to produce the intermediate and formula(27). Treatment of this intermediate with methanethiol in the presenceof a strong base such as sodium hydride produces the 3-methylthiomethylcompound of formula (28), which upon acid hydrolysis gives the3-methylthiomethyl-6-oxo-1-substitutedtrans-1,2,4a,5,6,7,8,8a-octahydroquinoline of formula (16-IV). Thesesteps are exemplified in Preparation 5. ##STR29##

Methods of preparing compounds of formulas (17) and (18) are illustratedin Reaction Scheme VIII. The starting material of formula (21) isdecarboxylated, using, for example, 10% potassium hydroxide, asillustrated in Preparation 6, to produce the intermediate of formula(29). Reduction of the 4-oxo group of the intermediate of formula (29)with L-Selectride® (lithium tri-sec-butylborohydride, 1.0M intetrahydrofuran) produces a compound of formula (30) that, on acidhydrolysis, gives therac-(4β,4aα,8aβ)-4-(6-oxo-1-substituted-decahydroquinolin)-ol of formula(17-I). This reaction is illustrated in Preparation 8. Reduction of the4-oxo group of the intermediate of formula (29) with lithium in ammoniaproduces a compound of formula (30) that, on acid hydrolysis, gives therac-(4α,4aα,8aβ)-4-(6-oxo-1-(substituted)decahydroquinolin)-ol offormula (18-I). This reaction is illustrated in Preparation 7.

Reacting the ketone of formula (29) with hydroxylamine produces theoxime of formula (31). Reduction of the oxime with lithium aluminumhydride produced a 1:1 mixture of the rac-(4α,4aα,8aβ) andrac-(4β,4aα,8aβ)-6-oxo-1-substituted-decahydroquinolin-4-amine acetalracemates of formula (32). The two diastereomers can be separated on asilica gel column. This preparation is illustrated in Preparation 9.

The 4-alkanoylamino and 4-aminosulfonylamino derivatives of formulas(17) and (18) are prepared from the 4-amino compounds without affectingthe stereochemistry of the compounds. Accordingly, the rac-(4β,4aα,8aβ)-4-alkanoylamino-6-oxo-1-substituted -decahydroquinoline acetalracemates of formula (17-III) are prepared by acylating the acetal ofthe correspondingrac-(4β,4aα,8aβ)-6-oxo-1-substituted-decahydroquinolin-4-amine, andhydrolyzing the resulting compounds of formula (34). This is illustratedin Preparation 12. The rac-(4α,4aα,8aβ)-4 alkanoylamino-6-oxo-1-substituted-decahydroquinoline acetal racemates of formula(18-III) are prepared in the same way, starting with therac-(4α,4aα,8aβ)-4-amine compound of formula (32) as illustrated inPreparation 11.

Similarly, sulfonylation of the appropriate racemate of the 4-aminocompound of formula (32) with a compound of the formula R⁹ R¹⁰ NSO₂ Cl,produces the corresponding racemate of formula (33), which on acidhydrolysis produces the corresponding racemate of formula (17-II) or(18-II), as illustrated in Preparation 10 for the (4α,4aα,8aβ) racemate.##STR30##

Preparation of racemates of formula (19), which are useful in preparingfinal-products of formula (2), is illustrated in Reaction Scheme IX. Inthe first step, the α,β-unsaturated ester of formula (24) is reducedusing lithium in ammonia to produce therac-(3α,4aα,8aβ)-3-(4-oxo-1-substituted-decahydroquinoline)-methanolacetal of formula (35) (only one enantiomer is shown). This reaction isexemplified in Preparation 13. Acid hydrolysis of the intermediate offormula (35) produces therac-(3α,4aα,8aβ)-3-(6-oxo-1-substituted-decahydroquinoline)methanols offormula (19-II). This reaction is exemplified in Preparation 14.rac-(3α,4aα,8aβ)-3-Methoxymethyl-6-oxo-1-substituted-decahydroquinolines of formula (19III) are preparedusing methods exemplified in Preparation 15.rac(3α,4aα,8aβ)-3-Methylthiomethyl-6-oxo-1-substituted-decahydroquinolines of formula (19-IV) are preparedusing methods exemplified in Preparation 16.

The rac-(3α,4aα,8aβ)-6-oxo-1-substituted-decahydroquinoline-3-carboxylic acid esters of formula(19) wherein R² is CO₂ R⁶ can be prepared by oxidizing the correspondingalcohol of formula (19-II) to provide the carboxylic acid of formula(19) wherein R² is CO₂ H, and then esterifying. Alternatively, theesters of formula (19) wherein R² is CO₂ R⁶ can be obtained byepimerizing the acetal of the diasteromeric ester, as described below.##STR31##

Preparation of racemates of formula (20), is illustrated in ReactionScheme X. These intermediates are useful in preparation of compounds offormula (3). In the first step, the α,β-unsaturated ester of formula(24) is hydrogenated using Raney® nickel as catalyst, to produce theacetal ofrac-(3β,4aα,8aβ)-6-oxo-3-substituted-decahydroquinoline-3-carboxylicacid ester of formula (39). This reaction is illustrated in Preparation19. Hydrolysis of the acetal of formula (39) gives the correspondingketone of formula (20-I), as exemplified in Preparation 24. Reducing thecarboxylic acid ester function of the acetal of formula (39) usinglithium aluminum hydride gives the corresponding alcohol of formula (40)as exemplified in Preparation 20. The (3β,4aα,8aβ) alcohol of formula(40) is converted to the intermediate of formula (20-II) (Preparation21), formula (20-III) (Preparation 22), and formula (20-IV) Preparation23), using the procedures previously discussed. In each case, theprocedures used do not affect the configuration of the carbon atom towhich the R² substituent is attached.

The rac-(3β,4aα,8aβ) esters of formula (39) can be epimerized to providethe corresponding (3α,4aα,8aβ) esters by treating the esters of formula(39) with lithium diisopropylamide, followed by protonation asillustrated in Preparation 17. This intermediate can then be hydrolyzedto provide rac-(3α,4aα,8aβ)-6-oxo-1-substituted-decahydroquinoline-3-carboxylic acid ester offormula (19-I) ##STR32## as exemplified in Preparation 18.

The intermediates of formula (21) in Reaction Scheme VII are prepared bythe process illustrated in Reaction Scheme XI, wherein R¹⁵ and R¹⁶ areC₁ -C₃ alkyl or combine to form --(CH₂)_(n) -- where n is 2-4, and R¹⁷is methyl or ethyl, and R¹ and R⁶ are as defined previously. Thesereactions are exemplified in Preparations 25-29 and Example 39. Theintermediates of formula (21) also form a part of the invention.##STR33##

The intermediates of formula (44) in Reaction Scheme XI are prepared bythe method described by Pariza, et al., Synthetic Communications, 13,243 (1983).

The invention is further illustrated by the following Preparations andExamples.

Preparation 1 Ethyl1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',-4a',5',6',7',8',8a'-octahydroquinoline)]-3'-carboxylateA. Reduction of ethyl 4-oxo-1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate

A solution of 63.3 g (0.2 mole) of ethyl4-oxo-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylatein 500 ml of ethanol was cooled to 0° C. To this was added a solutioncomprising 2.4 g (.06 mole) of sodium borohydride (NaBH₄) in 500 ml ofethanol. The mixture was stirred for 15 minutes at 0° C., then it waspoured into water. The product was extracted into methylene chloride,which was then dried using sodium sulfate and evaporated to give 64.1 gof product represented by four spots on TLC. This was passed through asilica gel column with EtOAc/hexane (1:2), followed by EtOAc containinga trace of NH₄ OH. The fractions containing the two compoundsrepresented by the TLC spots with the higher R_(f) 's were combined togive 17.1 g of product (hereinafter designated as Sample 1). Thefractions containing the two compounds represented by the TLC spots withlower R_(f) 's were combined to give 45.9 of product (hereinafterdesignated as Sample 2).

Samples 1 and 2 were composed of different isomers of ethyl4-hydroxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate.The two samples were reacted separately in the following steps B and C.

B. Sulfonylation of ethyl 4-hydroxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate

Sample 1 of ethyl 4-hydroxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate (17.1 g,0.05 mole) from step A was dissolved in 100 ml of pyridine. Then 9.0 g(0.078 mole) of methanesulfonyl chloride was added to the mixture, andthis was stirred overnight. The pyridine was evaporated to give a brownfoam identified as ethyl 4-methylsulfonyloxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate(Sample 1). This was carried over for use in step C.

Sample 2 of ethyl 4-hydroxy-1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate fromstep A (45.9 g, 0.14 mole) was sulfonylated using the foregoingprocedure, except that three times the relative amount ofmethanesulfonyl chloride was used, to produce a black foam identified asethyl4-methylsulfonyloxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate(Sample 2).

C. Elimination of methanesulfonic acid from ethyl4-methylsulfonyloxy-1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate

To a solution of Sample 1 of ethyl 4-methylsulfonyloxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate (from step B) in 150 ml ofethanol was added 100 ml of a 1N solution of sodium ethoxide in ethanol.The mixture was stirred at room temperature overnight. Then another 100ml of the 1N ethoxide solution was added, and this was stirredovernight. The mixture was then poured onto ice, and the hydrogen ionconcentration was adjusted to pH 10. The product was extracted intomethylene chloride, and the resulting methylene chloride solution wasdried with sodium sulfate and evaporated to give 19.2 g of a dark brownoil. This was passed through a silica gel column with hexane/THF (4:1)containing a trace of NH₄ OH. Fractions shown by TLC to contain ethyl1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]-3'-carboxylatewere combined to give 10.5 g.

Later fractions were combined to give 1.4 g of a mixture comprising thedesired product and an impurity. This mixture was passed through asilica gel column with hexane/THF (3:1) containing a trace of NH₄ OH.Fractions shown by TLC to contain ethyl 1'-propyl-trans-spiro-[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]-3'-carboxylate were combined to give0.8 g of material, making a total of 11.3 g (Sample 1).

Sample 2 of ethyl4-methylsulfonyloxy-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylatefrom step (B) was subjected to the same process as above, except thatone half the relative amount of sodium ethoxide and one half thereaction time was used, producing 18.3 g of ethyl 1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]-3'-carboxylate.

Preparation 23-Hydroxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-oneA. Reduction of ethyl1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]-3'-carboxylate

To a solution of 2.2 g (7.1 mmole of ethyl1'-propyl-trans-spiro[1,3-dioxolane-2,6'-1',2',4a',5',-6',7',8',8a'-octahydroquinoline)]-3'-carboxylate in toluene(100 ml) at 0° C., 17.8 ml of a 1M solution of diisobutylaluminumhydride in methylene chloride was added slowly. After stirring 10minutes, 100 ml of methanol was added and the mixture was stirred atroom temperature for 45 minutes. The precipitate was removed byfiltering the mixture through a pad of celite.

The filtrate was evaporated and the residue passed through a silica gelcolumn with 5% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. The fractionsshown by TLC to contain3'-(1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octa-hydroquinoline)]-methanol were combined to give 1.5 g of anoil which solidified upon setting.

B. Hydrolysis of3'-(1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)])methanol

A solution of 1.6 g of 3'-(1'-propyl-trans-spiro-[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)])methanol in 100 ml of water and 20ml of concentrated hydrochloric acid was prepared and stirred for 1hour. It was then poured into a water and ice mixture. The resultingmixture was made basic. Then the product was extracted into a solutionof CHCl₃ /i-PrOH (3:1), which was evaporated to give 1.3 g of3-hydroxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one.

EXAMPLE 17-(5-Propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo-[3,4-g]quinoline)methanol

A solution of 1.8 g (15.7 mmole) of potassium tert-butoxide in 20 ml ofTHF was cooled to 0° C. To this was added a solution of 1.3 g (5.8mmole) of3-hydroxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one(Preparation 2), 1.7 g (23.3 mmole) of ethyl formate, and 40 ml of THF.The mixture was warmed to room temperature and stirred for 3 hours,after which 4 ml of hydrazine was added and the hydrogen ionconcentration was adjusted to pH 9-10. The mixture was stirred overnightat room temperature and, then poured into water. The product wasextracted into a solution of CHCl₃ /i-PrOH (3:1), which was thenevaporated to give 1.3 g of a brown gum. This was purified on a silicagel column with 10% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH, yielding400 mg of material, which was dissolved in CHCl₃. A solid crystallizedout of the solution, and hexane was added to increase crystallization ofthe product. The crystals were separated by filtration, providing 390 mgof material identified as a trichloromethane complex of the titlecompound. M.P. 112°-115° C.

Analysis Calcd: C, 49.08; H, 6.05; N, 11.51, Cl, 29.00.

Found: C, 49.46; H, 5.67; N, 11.33, Cl, 28.83.

Mass spectrum: 246, 218, 152, 118.

EXAMPLE 28-(2-Amino-6-propyl-trans-5,5a,6,7,9a,10-hexahydropyrido[2,3-g]quinazoline)methanol

To a solution of 1.5 g (6.7 mmole) of3-hydroxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one(Preparation 2) in 100 ml of toIuene there was added 4.5 ml (16.9 mmole)of tris -(dimethylamino)methane. The mixture refluxed for 1 hour. Thetoluene was evaporated to give a brown oil. To a solution of thismaterial in 75 ml of ethanol was added a suspension of 1.2 g (6.7 mmole)of guanidine carbonate in 75 ml of ethanol. The mixture was heated toreflux for 3 hours, allowed to stand at room temperature overnight, andwas then poured into water. The product was extracted from the aqueousmixture into CHCl₃ /i-PrOH (3:1). The organic solvent was evaporated,giving a brown semi-solid product, which was put in a vacuum desiccatorovernight. The resulting product weighed 1.9 g. It was passed through asilica gel column with 10% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH.The fractions shown by TLC to contain the product were combined to give0.5 g of a yellow solid. This was taken up in a mixture of methanol andmethylene chloride. The solution was boiled down and ethyl acetate wasadded until crystals began to form. The solution was cooled and thesolid collected by filtration and dried in a vacuum desiccator, giving0.4 g of the title product.

Analysis Calcd: C, 65.67; H, 8.08; N, 20.42.

Found: C, 65.44; H, 7.80; N, 20.29.

Mass spectrum: 287, 273, 245, 198, 166, 152, 122.

Infrared spectrum (KBr): 3380, 3316, 3192, 1642, 1593, 1562, 1476, 1030cm⁻¹.

Preparation 3 Ethyl6-oxo-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinoline-3-carboxylate

A solution comprising 4.0 g (26 mmole) of ethyl1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',-4a',5',6',7',8',8a'-octahydroquinoline)-3'-carboxylate (4.0 g) (Preparation 1), 40 ml ofconcentrated HCl, and 100 ml of water was stirred at room temperaturefor one hour, and then poured onto ice. The hydrogen ion concentrationwas adjusted to pH 10, and the product was extracted into a solution ofCHCl₃ /i-PrOH (3:1), which was then dried with sodium sulfate andevaporated to give 3.5 g of the title product.

EXAMPLE 3 Ethyl2-amino-5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo[4,5-g]quinoline-7-carboxylate

A solution comprising 3.5 g (13 mmole) of ethyl6-oxo-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinoline-3-carboxylate(Preparation 3), 100 ml of acetic acid and 5.2 g (20 mmole) of a 31%solution of hydrogen bromide in acetic acid was prepared. 2.5 g (16mmole) of bromine was slowly added, and the mixture was stirred at roomtemperature for 15 minutes. The acetic acid was then stripped off, andthe residue was taken up in ethanol. To this solution 1.1 g (15 mmole)of thiourea was added, and the mixture was refluxed for 4 hours. Themixture was then cooled to room temperature, and poured into water. Theproduct was extracted into a solution of CHCl₃ /i-PrOH (3:1), which wasthen dried with sodium sulfate and evaporated to give 4.3 g of product.This was passed through a silica gel column with 5% MeOH/CH₂ Cl₂containing a trace of NH₄ OH. The fractions shown by TLC to contain thetitle compound were combined to give 2.6 g of material.

Proton nmr (CDCl₃) 90 MHz: 6.70 (s, 1H), 4.15 (q, 2H), 1.30 (t, 3H),0.90 (t, 3H).

EXAMPLE 4 Ethyl5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline-7-carboxylate

A solution of 0.5 g (1.5 mmole) of ethyl2-amino-5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline-7-carboxylate(Example 3) in 50 ml of 85% phosphoric acid was cooled to 0° C. Then 110mg (1.8 mmole) of sodium nitrite dissolved in as small an amount ofwater as possible was slowly adeed under the surface of the reactionmixture. The resulting mixture was added dropwise to 50 ml of 50%hypophosphorous acid (H₃ PO₂) at 0° C. The mixture was stirred at roomtemperature until gas evolution ceased. This took about 1 hour. Themixture was poured onto ice, and the hydrogen ion concentration of themixture was adjusted to pH 11. Water was added to dissolve thepreoipitate that formed; then the product was extracted into a solutionof CHCl₃ /i-PrOH (3:1). This solution was dried using sodium sulfate andevaporated to give 0.46 g of the title product.

Proton nmr (CDCl₃) 90 MHz: 8.52 (s, 1H), 6.79 (s, 1H), 4.18 (q, 2H),1.32 (t, 3H), 0.92 (t, 3H)

EXAMPLE 57-(5-Propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline)methanol

To a solution comprising 0.46 g (1.6 mmole) of ethyl5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline-7-carboxylate(Example 4) in 100 ml of THF at 0° C., there was added 7.8 ml (7.8mmole) of a 1M solution of diisobutylaluminum hydride in methylenechloride. To this mixture, 100 ml of methanol was added, and theresulting mixture was stirred for 1 hour. The precipitate was removed byfiltering the mixture through a pad of celite. The filtrate wasevaporated, and the residue was passed through a silica gel column with5% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH, providing the titlecompound. This was converted to the dihydrochloride salt, which was thenrecrystallized from MeOH/EtOAc to give a tan solid, M.P.>235° C.,identified as7-(5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline)-methanoldihydrochloride.

Mass spectrum: m/e=264.

Preparation 43-Methoxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-oneA. Methylation of3'-(1'-propyl-trans-spiro[1,3'dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]methanol

Ammonia (300 ml) was distilled into a flask through a BaO column. Firstsodium metal (580 mg, 25.3 mmole) and then a trace of FeCl₃ were addedto the ammonia.3'-(1'-propyl-trans-spiro1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)])methanol(2.7 g, 10.1 mmole) was added, and the mixture was stirred for 3 hours.Methyl iodide (4.3 g, 30.3 mmole) was added to the mixture, which wasthen stirred an additional 2 hours. The mixture was then added to water.The product was extracted into methylene chloride, which was then driedwith sodium sulfate and evaporated to give 2.9 g of product. This wasrun through a silica gel column with 3% MeOH/CH₂ Cl₂ containing a traceof NH₄ OH. The fractions shown by TLC to contain3-methoxymethyl-1'-propyl-trans-spiro-[1,3-dioxolane-2,6'-(1',2',4a',5', 6',7',8',8a'-octahydroquinoline)]were combined to give 2.2 g of product.

B. Hydrolysis of 3'-methoxymethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]

A solution of 2.2 g of3'-methoxymethyl-1'-propyl-trans-spiro1,3-dioxolane-2,6'-(1',2',4a',5',6'-7',8',8a'-octahydroquinoline)] in 100 ml of water and 20 ml ofconcentrated hydrochloric acid was prepared and stirred for 1 hour. Itwas then poured onto ice. The hydrogen ion concentration was adjusted topH 10, and the product extracted into a solution of CHCl₃ /i-PrOH (3:1).This was dried with sodium sulfate and evaporated to give 1.9 g of3'-methoxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one.

EXAMPLE 68-(Methoxymethyl)-6-propyl-trans-5,5a,6,7,9a,10-hexhydropyrido[2,3-g]quinazolin-2-amine

The title product was prepared using the procedure of Example 2 and thecompound of Preparation 4 as starting material.

Analysis Calcd: C, 66.64; H, 8.39; N, 19.43.

Found: C, 66.76; H, 8.20; N, 19.52.

Mass spectrum: 287, 259, 243, 198, 166, 136.

EXAMPLE 77-(Methoxymethyl)-5-propyl-4,4a,5,6,8a,9-trans-hexa-hydro-2H-pyrazolo3,4-g]quinoline

To a solution of 850 mg (3.6 mmole) of3-methoxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-oein 50 ml of toluene was added 1.3 g (9.0 mmole) oftris(dimethylamino)methane. This refluxed for 2 hours, then the toluenewas evaporated and the residue was taken up in 50 ml of ethanol. Tothis, 2 ml of hydrazine was added, and the resulting mixture was stirredovernight at room temperature. The mixture was poured into water and theproduct was extracted into methylene chloride. The methylene chloridesolution was dried using sodium sulfate and evaporated to give 950 mg ofa light brown oil. This was passed through a silica gel column with 5%MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. The fractions shown by TLC tocontain the title compound were combined to give a yellow oil, whichcrystallized on setting. This was recrystallized from EtOAc/hexane togive 550 mg of the title compound.

Analysis Calcd: C, 68.93; H, 8.87; N, 16.08.

Found: C, 68.99; H, 8.64; N, 16.11.

Mass spectrum: 260, 232, 216, 166, 136.

Preparation 53-Methylthiomethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-oneA. Conversion of3'-(1'-propyl-trans-spiro1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]methanol to the corresponding allylicchloride

Chlorine gas was bubbled through a solution of 7.5 g (28.5 mmole) oftriphenylphosphine in 75 ml of tetrachloromethane until the solutionbegan to turn yellow. The tetrachloromethane was then evaporated, andthe white solid residue was dissolved in 100 ml of DMF. To this solutionwas added a solution of 3.8 g (14.2 mmole) of3'-(1'-propyl-trans-spiro1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)])-methanol, and the resulting mixture wasstirred for 11/2 hours at room temperature, resulting in a solution of3'-chloromethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)] in DMF.

B. Substitution of methyl mercaptide for chloride in3'-chloromethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]

To 19.2 ml of methanethiol solution (3.5M in DMF) at 0° C. was added 2.2g of a 60% dispersion of sodium hydride in mineral oil. To this wasadded a solution of 1.6 g (5.6 mmole) of3'-chloromethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)] in 10 ml of DMF. The mixturewas allowed to warm to room temperature and was stirred for 3 hours,after which it was poured into water. The product was extracted intomethylene chloride, which was then dried with sodium sulfate andevaporated to give 2.6 g of product. This was passed through a silicagel column with 5% MeOH/CH₂ Cl₂. The fractions shown by TLC to contain3'-methylthiomethyl-1'-propyl-trans-spiro-[1,3-dioxolane-2,6'-(1',2',4a',5', 6',7',8'-8a'-octahydroquinoline)]were combined to give 1.7 g of product.

C. Hydrolysis of 3'-methylthiomethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]

A solution comprising 2.6 g of3'-methylthiomethyl-1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',-4a',5',6',7',8', 8a'-octahydroquinoline)] in 100 ml ofwater and 40 ml of concentrated HCl was stirred at room temperature for1 hour. The mixture was then poured over ice, and made basic with 50%sodium hydroxide. The product was extracted into a solution of CHCl₃/i-PrOH (3:1), which was evaporated to give 2.2 g of3-methylthiomethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one.

EXAMPLE 87-(Methylthiomethyl)-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo[3,4-g]quinoline

The title compound was prepared using the process of Example 1 and thecompound of Preparation 5 as starting material. M.P. 133°-134° C.

Analysis Calcd: C, 64.94; H, 8.36; N, 15.15; S, 11.56.

Found: C, 65.26; H, 8.26; N, 14.91; S, 11.30.

Mass spectrum: 276, 248, 230, 182, 136, 94.

Infrared spectrum (CHCl₃): 3466, 3240, 2964, 1375, 1136.

Proton nmr (CDCl₃) 270 MHz: 7.34 (s, 1H), 5.46 (s, 1H), 2.02 (s, 3H),0.93 (t, 3H).

EXAMPLE 97-(Methylsulfinylmethyl)-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo[3,4-g]quinoline

To a solution of 480 mg (1.7 mmole) of7-(methylthiomethyl)-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo[3,4-g]quinoline(Example 8) in 50 ml of methanol was added a solution of 740 mg (3.5mmole) of sodium metaperiodate in 20 ml of water. The mixture wasstirred for 1 hour at room temperature and then poured into water. Thehydrogen ion concentration was adjusted to pH 11, and then the productwas extracted into a solution of CHCl₃ /i-PrOH (3:1). The solvent wasevaporated to give 0.47 g of product, which was passed through a silicagel column with 7-10% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. Thefractions shown by TLC to contain the title compound were combined togive 230 mg of a foam.

Proton nmr (CDCl₃) 270 MHz: 7.34 (s, 1H), 5.72 (s, 1H), 2.62 (s, 3H),0.93 (t, 3H).

Mass spectrum 292, 261, 247, 230, 218, 200, 170, 152, 136.

EXAMPLE 108-(Methylthiomethyl)-6-propyl-trans-5,5a,6,7,9a,10-hexahydropyrido[2,3-g]quinazolin-2-amine

The title compound was made using the procedure of Example 2 and thecompound of Preparation 5 as starting material.

Mass spectrum: 303, 275, 257, 227, 213, 198, 182.

Infrared spectrum (CHCl₃): 3422, 2936, 1607, 1562, 1457.

Proton nmr (CDCl₃) 270 MHz: 8.08 (s, 1H), 5.48 (s, 1H), 4.89 (s, 2H),2.01 (s, 3H), 0.94 (t, 3H).

The maleate salt was made of a 400 mg portion of the title compound. Thesalt was recrystallized from MeOH/EtOAc, producing 270 mg of product,which was then dissolved in warm MeOH. Activated carbon was added andthe mixture was filtered while hot. The residue was recrystallized togive 90 mg of the maleate salt of the title compound as yellow crystals.

Analysis Calcd: C, 57.12; H, 6.71; N, 13.32.

Found: C, 57.35; H, 6.84; N, 13.32.

EXAMPLE 118-(Methylsulfinylmethyl)-6-propyl-trans-5,5a,6,7,9a,10-hexahydropyrido[2,3-g]quinazolin-2-amine

The title compound was prepared following the procedure of Example 9 andusing the compound of Example 10 as the starting material.

Proton nmr (DMSO_(d6)) 270 MHz: 8.02 (s, 1H), 5.64 (s, 1H), 2.32 (s,3H), 0.87 (t, 3H).

Mass spectrum: 273, 256, 245, 227, 152, 136.

Preparation 61-Propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one

A solution of 30.0 g of ethyl4-oxo-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylatein 180 ml of methanol was prepared. To this was added 120 ml of a 10%solution of potassium hydroxide in methanol. The mixture refluxedovernight, and was then cooled to room temperature and poured onto ice.The product was extracted into methylene chloride, which was then driedwith sodium sulfate and evaporated to give 22.1 g of a yellow oil.(Yield 94.6%)

Preparation 7rac-(4β,4aα,8aβ)-4-Hydroxy-1-propyl-decahydroquinolin-6-one A.Stereoselective reduction of 1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one

A solution comprising 19.8 ml (19.8 mmole) of L-Selectride® (a 1.0Msolution of lithium tri-sec-butylborohydride in tetrahydrofuran) and 100ml of tetrahydrofuran was cooled to -78° C. To this solution was slowlyadded a solution of 2.5 g (9.9 mmole) of1-propyl-1-trans-spiro[decahydro-quinoline-6,2'-(1',3'-dioxolan)]-4-one(Preparation 6). The resulting mixture was stirred for 45 minutes. Waterwas then added until gas evolution ceased. Then approximately 2 g oftrimethylamine-N-oxide was added, and the mixture was stirred for 21/2hours. The mixture was then poured into water, and it was confirmed thatthe mixture was basic. The product was extracted into methylenechloride, which was then dried with sodium sulfate and evaporated togive a red oil. This was passed through a silica gel column with 10%MeOH/CH₂ Cl₂ to give 1.5 g of an orange oil that was identified asrac-(4β,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-ol.

B. Hydrolysis ofrac-(4β,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxoln)]-4-ol

A solution comprising 1.5 g of rac-(4β,4aα,8aβ)-1-propylspirodecahydroquinoline-6,2'-(1',3'-dioxolan)]-4-ol, 20 ml ofconcentrated hydrochloric acid, and 100 ml of water was prepared andstirred for 1 hour at room temperature. The mixture was then made basicwhile cooled. The product was extracted into CHCl₃ /i-PrOH (3:1), whichwas then dried with sodium sulfate and evaporated to give 1.1 g of alight brown solid that was identified asrac-(4β,4aα,8aβ)-4-hydroxy-1-propyldecahydroquinolin-6-one. (Yield88.6%)

Preparation 8 rac-(4α,4aα,8aβ)-4-Hydroxy-1-propyldecahydroquinolin-6-oneA. Stereoselective reduction of 1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one

To a solution formed by adding 0.75 g (10.8 mmole) of lithium metal to500 ml of ammonia there was slowly added a solution comprising 9.1 g (36mmole) of 1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one (Preparation 6), 2.7 g (3.4 ml) of t-butyl alcohol,and 100 ml of THF. The mixture was stirred for 30 minutes, and thenwater was added dropwise until the color disappeared. Most of theammonia was evaporated, and the residue was poured into water. Theproduct was extracted into methylene chloride, which was dried withsodium sulfate and evaporated to give 20 9.1 g of a brown gum. This waspassed through a silica gel column with 5% MeOH/CH₂ Cl₂ containing atrace of NH₄ OH, followed by 10% MeOH/CH₂ Cl₂ when the product wasmostly off. The fractions shown by TLC to contain the same compound werecombined to provide 4.9 g of an amber oil, which was identified asrac-(4α,4aα,8β)-1-propyl-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-ol.

B. Hydrolysis ofrac-(4α,4aα,8aβ)-1-propylspiro[decahydro-quinoline-6,2'-(1',3'-dioxolan)]-4-ol.

A solution comprising 3.8 g of rac-(4α,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolan)-4-ol, 40 ml ofconcentrated HCl, and 200 ml of water was prepared and stirred for 1hour at room temperature. The mixture was then poured onto ice and madebasic with NaOH. The product was extracted into methylene chloride,which was then dried using sodium sulfate, and evaporated to give 3.5 gof an amber oil, which was identified asrac-(4α,4aα,8aβ)-4-hydroxy-1-propyldecahydroquinolin-6-one.

EXAMPLE 12rac-(4aβ,8β,8aα)-5-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-8-ol

A solution of 1.4 g (12.8 mmole) of potassium tert-butoxide in 20 ml oftetrahydrofuran was prepared and cooled to 0° C. To the solution wereadded 1.0 g (4.7 mmole) ofrac-(4β,4aα,8aβ)-4-hydroxy-1-propyl-decahydroquinolin-6-one (Preparation7), 1.4 g (19.0 mmole) of ethyl formate, and 20 ml of tetrahydrofuran.The mixture was stirred at room temperature for 1 hour, forming aslurry. Then 3 ml of hydrazine was added, the hydrogen ion concentrationwas adjusted to pH 9, and the mixture was stirred for an additional 2hours. The mixture was poured onto ice, and the product was extractedinto methylene chloride, which was dried with sodium sulfate andevaporated to give 400 mg of product. Additional product left in theaqueous layer was extracted into a solution of CHCl₃ /i-PrOH (3:1),which was dried with sodium sulfate and evaporated to give 680 mg ofproduct. The combined lots were run through a silica gel column with 20%MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. The fractions shown by TLC tocontain the product were combined to give 850 mg. The free base wasrecrystallized from MeOH/EtOAc providing 270 mg of the title product asa white powder. M.P. 153°-154° C.

Mass spectrum: 235, 219, 206, 159, 119, 107.

UV spectrum (EtOH): λ_(max) =222 nm.

Proton nmr (CDCl₃) 270 MHz: 7.34 (s, 1H), 4.34 (d, 1H), 0.88 (t, 3H).

Infrared spectrum (CHCl₂): 3450, 3225, 2947, 2875, 1078.

EXAMPLE 13rac-(4aβ,8α,8aα)-5-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-8-ol

The title product was produced using the process of Example 12 and theproduct of Preparation 8 as starting material.

Infrared spectrum (CHCl₃): 3470, 3234, 1450, 1084 cm⁻¹.

Proton nmr (CDCl₃) 270 MHz: 7.28 (d, 1H), 0.89 (t, 3H).

Mass spectrum: 235, 206, 140, 124.

EXAMPLE 14rac-(4aβ,8β,8aα)-2-Amino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolin-9-olmethanesulfonate (1:2)

To a solution of 1.1 g (5.2 mmole) ofrac-(4β,4aα,8aβ)-4-hydroxy-1-propyldecahydroquinolin-6-one (Preparation7) in 60 ml of toluene was added 1.9 g (13.0 mmole) oftris(dimethylamino)methane. The mixture refluxed for 1 hour, and wasthen evaporated to a brown residue. This was mixed with 50 ml ofethanol, and the mixture was added to a suspension of 0.95 g (5.2 mmole)of guanidine carbonate in 50 ml of ethanol. The mixture was refluxed for4 hours, then cooled, and poured into water. The product was extractedinto a solution of CHCl₃ /i-PrOH (3:1), which was then dried with sodiumsulfate and evaporated to give 1.3 g of a dark yellow gum. This waspassed through a silica gel column with 10% MeOH/CH₂ Cl₂ containing atrace of NH₄ OH. The fractions shown by TLC to contain the wantedmaterial were combined to give 0.63 g of a yellow solid. A salt wasobtained by adding methanesulfonic acid and recrystallizing fromMeOH/EtOAc, to provide 450 mg of the title product as a yellow powder.M.P. 238°-239° C.

Infrared spectrum (KBr): 3304, 3165, 2954, 1661, 1602, 1569, 1496 cm⁻¹.

Mass spectrum: 261, 244, 234, 215, 153.

EXAMPLE 15rac-(4aβ,8α,8aα)-2-Amino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolin-9-oldihydrochloride

The free base of the title compound was prepared using the procedure ofExample 14 and the compound of Preparation 8 as the starting material.

Mass spectrum: 262, 244, 234, 215, 153.

Infrared spectrum (KBr): 3380, 3320, 3166, 2980, 1653, 1599, 1565, 1487cm⁻¹.

Proton nmr (CDCl₃, DMSO_(d6)) 270 MHz: 8.00 (s, 1H), 0,90 (t, 3H).

UV spectrum (EtOH): λ_(max) =229.

The hydrochloride salt was then formed. M.P. 296°-298° C.

Analysis Calcd: C, 50.15; H, 7.22; N, 16.71; Cl, 21.15.

Found: C, 50.36; H, 7.45; N, 16.76; Cl, 21.15.

Preparation 9rac-(4α,4aα,8aβ)-1-Propyl-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amineand rac-(4β,4aα,8aβ)-1-propyl-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine A. Addition ofhydroxylamine to 1-propyl-trans-spiro-[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one

To a solution of 1.3 g (5.1 mmole) of 1-propyl-trans-spirodecahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one was added1.0 g (13.9 mmole) of hydroxylamine hydrochloride. The mixture wasstirred overnight at room temperature, then poured into water. Theproduct was extracted into methylene chloride, which was then dried withsodium sulfate and evaporated to give 1.4 g of a tan solid, which wasidentified as 1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one oxime.

B. Reduction of 1-propyl-trans-spirodecahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one oxime

A solution of 3.2 g (12 mmole) of 1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-one oxime in 50ml of tetrahydrofuran was slowly added to a suspension of 1.0 g (26mmole) of lithium aluminum hydride in 50 ml of tetrahydrofuran, and themixture was refluxed for 2 hours. Then 1 ml of water, 1 ml of 15% sodiumhydroxide in water, followed by an additional 3 ml of water were added,and the resulting mixture was stirred for a further 30 minutes. Then theprecipitate was filtered off through a pad of celite. The filtrate wasevaporated to give 2.8 g of product, which was run through a silica gelcolumn with THF/MeOH (3:1) containing a trace of NH₄ OH. The fractionsshown by TLC to contain the higher R_(f) material were combined to give0.97 g ofrac-(4β,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine.The fractions shown by TLC to contain the lower R_(f) material werecombined to give 0.8 g of rac-(4α,4aα,8aβ)-1-propylspiro-[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine. The fractions shownby TLC to contain both materials were combined to give 0.5 g of amixture of the two isomers.

Preparation 10rac-(4α,4aα,8aβ)-4-(Dimethylaminosulfonylamino)-1-propyl-decahydroquinolin-6-oneA. Sulfonylation ofrac-(4α,4aα,8aβ)-1-propylspiro-[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine

To a solution of 3.6 g (14 mmole) ofrac-(4α,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-aminein 100 ml of methylene chloride there was added 175 mg (1.4 mmole) of4-dimethylaminopyridine and 7.2 g (71 mmole) of triethylamine. To thismixture was added 2.4 g (17 mmole) of dimethylsulfamoyl chloride, andthe mixture was stirred 4 hours at room temperature. Then an additional2.4 g (17 mmole) of dimethylsulfamoyl chloride and 7.2 g (71 mmole) oftriethylamine were added and the mixture was stirred overnight at roomtemperature. The mixture was then poured into water and the product wasextracted into methylene chloride, which was then dried using sodiumsulfate and evaporated to give 3.8 g of product. This was passed througha silica gel column with 5% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH.The fractions shown by TLC to containrac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propyl-spiro[decahydroquinoline-6,2'-(1', 3'-dioxolane)] werecombined to give 2.3 g of product.

B.Hydrolysis ofrac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)].

A solution of 2.3 g (6.4 mmole) ofrac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propyl-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)] in 100 ml offormic acid was prepared and stirred overnight at room temperature. Themixture was then poured onto ice and the hydrogen ion concentration ofthe resulting mixture was adjusted to pH 10. Product was extracted intoa solution of CHCl₃ /i-PrOH (3:1), which was then dried using sodiumsulfate to give 2.1 g of rac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propyl-trans-decahydroquinolin-6-one.

EXAMPLE 16 rac-(4aβ,8α,8aα)-8-(Dimethylaminosulfonylamino)-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H -pyrazolo[3,4-g]quinolineethanolate

To a solution of 1.0 g (3.1 mmole) ofrac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propyl-trans-decahydroquinolin-6-one (Preparation 10) in 100 ml oftoluene was added 1.1 g (7.9 mmole) of tris(dimethylamino)methane. Themixture was refluxed for 45 minutes, then the toluene was removed andthe residue was taken up in 100 ml of ethanol. To this, 3 ml ofhydrazine was added, and the mixture was stirred overnight at roomtemperature. The mixture was poured into water. The product wasextracted into methylene chloride, which was then dried with sodiumsulfate and evaporated to give 1.1 g of product. This was passed througha silica gel column with 7∵10% MeOH/CH₂ Cl₂ containing a trace of NH₄OH. The fractions shown by TLC to be the product were combined to give ayellow foam.

Mass spectrum: m/e=341.

UV; λ_(max) =219, ε=6278.3.

This was recrystallized from EtOH/EtzO to give 360 mg of the titlesolvate.

Analysis Calcd: C, 52.69; H, 8.58; N, 18.07.

Found: C, 52.44; H, 7.28; N, 18.02.

EXAMPLE 17 rac-(5aβ,8α,8aα)-9-(Dimethylaminosulfonylamino)-6-propyl-trans-5,5a,6,7,9,9a,10-octahydropyrido[2,3-g]quinazolin-2-amine

To a solution of 1.1 g (3.5 mmole) ofrac-(4α,4aα,8aβ)-4-(dimethylaminosulfonylamino)-1-propyldecahydroquinolin-6-one (Preparation 10) in 100 ml of toluenewas added 1.3 g (8.7 mmole) of tris(dimethylamino)methane. This wasrefluxed for 45 minutes. The toluene was removed and the residue wastaken up in 100 ml of ethanol. To this, 250 mg (4.2 mmole) of guanidinewas added, and the mixture was stirred at room temperature overnight.Then another 240 mg (4.2 mmole) of guanidine was added, and the mixturewas heated at 50° C. for 2 hours, after which it was poured into water.The product was extracted into a solution of CHCl₃ /i-PrOH (3:1), whichwas then dried using sodium sulfate and evaporated to give 1.2 g ofproduct. This was run through a silica gel column with 5% MeOH/CH₂ Cl₂containing a trace of NH₄ OH. The fractions shown by TLC to contain theproduct were combined to provide g of material, which was recrystallizedfrom Et₂ O to give 380 mg of the ethanol solvate of the title compound.

UV spectrum (EtOH): λ_(max) =229, ε=14,180

Mass spectrum: m/e=368.

When heated at 110° C. the solvate decomposed and the ethanol was drivenoff leaving the title compound.

Analysis Calcd: C, 52.15; H, 7.66; N, 22.81.

Found: C, 52.33; H, 7.57; N, 22.65.

M.P. 201° C. (decomposed).

Preparation 11rac-(4α,4aα,8aβ)-4-Acetylamino-1-propyldecahydroquinolin-6-on A.Acylation ofrac-(4α,4aα,8aβ)-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine

To a solution of 1.4 g (5.5 mmole) ofrac-(4α,4aα,8aβ)-1-propylspirodecahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine in 50 ml of pyridine was added 67 mg(0.55 mmole) of 4-dimethylaminopyridine and 1.4 g (13.8 mmole) oftriethylamine. The mixture was cooled to 0° C. and 0.5 g (6.6 mmole) ofacetyl chloride was added. The mixture was warmed to room temperature,stirred overnight, and poured into water. The product was extracted intomethylene chloride, which was then dried using sodium sulfate andevaporated to give 1.5 g of product. This was passed through a silicagel column with 5% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. Thefractions shown by TLC to contain rac-(4α,4aα,8aβ) -4-acetylamino-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)] were combinedto give 1.15 g of a white solid.

B. Hydrolysis ofrac-(4α,4aα,8aβ)-4-acetylamino-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]

A solution was prepared of 1.1 g ofrac-(4α,4aβ,-8aβ)-4-acetylamino-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]20 ml of concentrated hydrochloric acid and 100 ml of water. The mixturewas stirred at room temperature for 1 hour and then poured onto ice. Thehydrogen ion concentration of the resulting mixture was adjusted to pH11. The product was extracted into a solution of CHCl₃ /i-PrOH (3:1),which was then evaporated to give 0.97 g of an off-white solididentified byrac-(4α,4aα,8aβ)-4-acetylamino-1-propyldecahydroquinolin-6-one.

EXAMPLE 18rac-(4aβ,8α,8aα)-8-Acetylamino-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline

The title compound was prepared using the procedure of Example 12 andthe compound of Preparation 11 as the starting material.

Mass spectrum: m/e=276.

Analysis for dihydrate, Calcd: C, 46.76; H, 7.85; N, 14.54.

Found: C, 46.50; H, 7.12; N, 14.78.

EXAMPLE 19rac-(4aβ,8α,8aα)-5-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-8-amine

The title product was prepared by hydrolysis of the compound of Example18.

Mass spectrum: m/e=235.

UV spectrum: λ_(max) =221; ε=5670.

Infrared spectrum (KBr): 3270, 3245, 2900, 1680 cm⁻¹.

Preparation 12rac-(4β,4aα,8aβ)-4-Acetylamino-1-propyldecahydroquinolin-6-one

The title product was prepared by acylatingrac-(4β,4aα,8aβ)-1-propylspirodecahydroquinoline-6,2'-(1',3'-dioxolan)]-4-amine (Preparation 9), then hydrolyzing theresulting rac-(4β,4aα,8aβ)-4-acetylamino-1-propyl-spirodecahydroquinoline-6,2'-(1',3'-dioxolane)]using the procedures of Preparation 11.

EXAMPLE 20rac-(4aβ,8β,8aα)-8-Acetylamino-5-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline

The title compound was prepared using the procedure of Example 12 andthe compound of Preparation 12 as the starting material. Thedihydrochloride salt was then formed and recrystallized from MeOH/EtOAC.

Mass spectrum: m/e=276.

Analysis Calcd: C, 51.58; H, 7.50; N, 16.04.

Found: C, 51.32, H, 7.38; N, 15.81.

EXAMPLE 21rac-(4aβ,8β,8aα)-5-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinolin-8-amine

The title product was prepared by acid hydrolysis of the compound ofExample 20. The trihydrochloride salt was then formed and recrystallizedfrom MeOH/EtOAC.

Mass spectrum: 235, 215, 149, 80.

EXAMPLE 227-(2-Amino-5-propyl-trans-4,4a,5,6,8a,9-hexahydrothiazolo-[4,5-g]quinoline)methanol

The product of Example 3 (2.6 g, 8.1 mmole) was reduced using 5equivalents of diisobutylaluminum hydride in methylene cloride toproduce the title product (1.7 g).

Mass spectrum: m/e=323, 279.

EXAMPLE 23 7-57-(2-Methyl-5-propyl-trans-4,4a,5,6,8a,g-hexahydro-2H-pyrazolo[3,4-g]quinoline)methanoland 7-(1-Methyl-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-1H-pyrazolo[3,4-g]-quinoline)methanol

A solution of 650 mg (5.8 mmole) of potassium tert-butoxide in 10 ml ofTHF was cooled to 0° C. To this was added a solution of 480 mg. (2.1mmole) of3-hydroxymethyl-1-propyl-trans-1,2,4a,5,6,7,8,8a-octahydroquinolin-6-one(Preparation 2), 600 mg (8.5 mmole) of ethyl formate, and 15 ml of THF.The mixture was warmed to room temperature and stirred for 5 hours,after which 2 ml of methyl hydrazine was added and the hydrogen ionconcentration was adjusted to pH 9 while the mixture was cooled. Themixture was stirred overnight at room temperature and, then poured intowater. The product was extracted into a solution of CHCl₃ /i-PrOH (3:1),which was then evaporated to give 560 mg. of product, represented by twospots on TLC. The two isomers were separated on a silica gel columnusing 7% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. The fractions shownby TLC to contain7-(2-methyl-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo[3,4-g]quinoline)methanolwere combined, and the tosylate salt of this product was formed. Thiswas recrystallized from MeOH/EtOAC, giving the tosylate salt of7-(2-methyl-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-2H-pyrazolo[3,4-g]-quinoline)methanol as a yellow solid. M.P. 232°-233° C.

The fractions shown by TLC to contain7-(1-methyl-5-propyl-trans-4,4a,5,6,8a,9-hexahydro-1H-pyrazolo[3,4-g]quinoline)methanolwere combined, and the hydrochloride salt of this product was formed.This was recrystallized from MeOH/EtOAc to give the hydrochloride saltof7-(1-methyl-5-propyl-trans-4,4a,5,6,-8a,9-hexahydro-1H-pyrazolo[3,4-g]quinoline)methanolas a light yellow solid. M.P. 215°-216° C.

Preparation 13rac-(3α,4aα,8aβ)-3-(1-Propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanol

Ammonia (125 ml) was distilled through a BaO column, and 450 mg (65mmole) of lithium was dissolved therein. To this solution 2.0 g (6.5mmole) of ethyl 1'-propyl-trans-spiro[1,3-dioxolane-2,6'-(1',2',4a',5'-6',7',8',8a'-octahydroquinoline)]-3'-carboxylate (Preparation 1), 1.2 g(26 mmole) of ethanol, and 30 ml of THF were added slowly. The mixturewas stirred for 30 minutes, and then ethanol was slowly added until thecolor faded. Nitrogen was blown over the mixture to evaporate theammonia. The residue was taken up in water. The product was extractedfrom the aqueous mixture into methylene chloride, which was then driedusing sodium sulfate, and evaporated to give 1.5 g of product. This waspassed through a silica gel column with 3→5% MeOH/CH₂ Cl₂ containing atrace of NH₄ OH. The fractions shown by TLC to contain the title productwere combined yielding 1.2 g thereof.

Preparation 14rac-(3α,4aα,8aβ)-3-Hydroxymethyl-1-propyldecahydroquinoline-6-one

A solution of 1.2 g of rac-(3α,4aα,8aβ)-3-(1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])-methanol(Preparation 13) in 50 ml of water and 20 ml of concentratedhydrochloric acid was prepared and stirred for 1 hour. It was thenpoured into ice. The resulting mixture was made basic. Then the productwas extracted into a solution of CHCl₃ /i-PrOH (3:1), which was driedusing sodium sulfate and evaporated to give 0.99 g of rac-(3α,4aα,8aβ)-3-hydroxymethyl-1-propyldecahydroquinoline-6-one.

EXAMPLE 24rac-(4aβ,7α,8aα)-7-(5-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline)methanol

To a solution of 0.47 g (2.1 mmole) of rac-

(3α,4aα,8aβ)-3-hydroxymethyl-1-propyldecahydroquinoline-6-one(Preparation 14) in 50 ml of toluene there was added 1.4 ml (5.2 mmole)of tris(dimethylamino)methane. The mixture refluxed for 3 hours. Thetoluene was evaporated, and to a solution of this material in 50 ml ofmethanol was added 3 ml of hydrazine. The mixture was stirred at roomtemperature overnight, and was then poured into water. The product wasextracted from the aqueous mixture into CHCl₃ /i-PrOH (3:1). This wasdried with sodium sulfate and evaporated giving an orange semi-solidproduct, which was passed through a silica gel column with 5→7% MeOH/CH₂Cl₂ containing a trace of NH₄ OH. The fractions shown by TLC to containthe product were combined to give 300 mg of the title compound. This wasconverted to the hydrochloride salt, which was recrystallized fromMeOH/EtOAc.

Analysis Calcd: C, 52.18; H, 7.82; N, 13.04.

Found: C, 52.07; H, 7.92; N, 13.07.

EXAMPLE 25rac-(5aβ,8α,9aα)-8-(2-amino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazoline)methanol

To a solution of 0.5 g (2.2 mmole) ofrac-(3α,4aα,8aβ)-3-hydroxymethyl-1-propyldecahydroquinoline-6-one(Preparation 14) in 50 ml of toluene there was added 1.5 ml (5.6 mmole)of tris(dimethylamino)methane. The mixture refluxed for 2 hours. Thetoluene was evaporated, and to a solution of the residue in 75 ml ofethanol was added a suspension o 130 mg (2.2 mmole) of guanidine in 50ml of ethanol. The mixture was heated to reflux for 1 hour, stirred atroom temperature overnight, and was then poured into water. The productwas extracted from the aqueous mixture into CHCl₃ /i-PrOH (3:1) whichwas then dried using sodium sulfate and evaporated, giving 590 mg of ayellow solid. This was passed through a silica gel column with 7%MeOH/CH₂ Cl₂ containing a trace of NH₄ OH. The fractions shown by TLC tocontain the product were combined and recrystallized from MeOH/EtOAc,yielding 215 mg.

Mass spectrum: 276, 247, 204, 168, 154, 146, 136, 126.

Proton nmr (360 MHz) DMSOds: 7.98 (s,1H), 6.21 (s,2H), 0.82 (t,3H).

Preparation 15rac-(3α,4aα,8aβ)-3-Methoxymethyl-1-propyldecahydroquinoline-6-one

The title product was prepared using the procedures of Preparation 4 andthe product of Preparation 13 as the starting material.

EXAMPLE 26rac-(4aβ,7α,8aα)-7-Methoxymethyl-5-propyl-4,4a,5,6,7,8,-8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline

The title product was prepared using the procedure of Example 24 andrac-(3α,4aα,8aβ)-3-methylthiomethyl-1-propyldecahydroquinoline-6-one(Preparation 15) as the starting material. This was converted to thedihydrochloride salt and recrystallized with MeOH/CH₂ Cl₂ to give a tansolid.

Mass spectrum: 263, 248, 234, 169, 154, 140, 119, 71.

Analyss Calcd: C, 53.57; H, 8.09; N, 12.49.

Found: C, 53.53; H, 7.90; N, 12.42.

EXAMPLE 27rac-(5aβ,8α,9aα)-8-methoxymethyl-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrida-[2,3-g]quinazolin-2-amine.

The title product was prepared using the procedure of Example 25 andrac-(3α,4aα,8aβ) -3-methoxymethyl-1-propyldecahydroquinoline-6-one(Preparation 15) as the starting material. This was recrystallized fromMeOH/EtOAc.

Mass spectrum: 290, 275, 261, 245, 218, 179, 168, 154, 136, 122, 71.

Analysis Calcd: C, 66.17; H, 9.09; N, 19.29.

Found: C, 66.41; H, 9.25; N, 19.39.

Preparation 16rac-(3α,4aα,8aβ)-3-Methylthiomethyl-1-propyldecahydroquinolin-6-one A.Conversion ofrac-(3α,4aα,8aβ)-3-(1-propylspiro-[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanol (Preparation 13) to correspondingmethanesulfonate

A solution of 1 g (3.7mmole) ofrac-(3α,4aα,8aβ)-3-(1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanolin 25 ml of pyridine was cooled to 0° C. To this 0.55 g (4.8 mmole) ofmethanesulfonyl chloride was added, and the mixture was stirred at roomtemperature for 2 hours. The mixture was then poured into water, and thehydrogen ion concentration was adjusted to pH 10. The product wasextracted into methylene chloride, which was then dried to giverac-(3α,4aα,8aβ)-3-methylsulfonyloxymethl-1-propylspiro[decahydroquinolin-6,2'-(1',3'dioxolane)].

B. Substitution of methyl mercaptide for methylsulfonyloxy inrac-(3α,4aα,8aβ)-3-methylsulfonyloxymethyl-1-propylspiro[decahydroquinolin-6,2'-(1', 3'dioxolane)].

After rinsing 355 mg (7.4 mmole) of sodium hydride (55% in mineral oil)with hexane, it was suspended in 25 ml of DMF and 10.6 ml (37mmole) of a3.5M solution of methanethiol was added. An additional 4 ml (14 mmole)of the methanethiol was added, whereupon the solution turned a clearlight amber. This was cooled to 0° C. and therac-(3α,4aα,8aβ)-3-methylsulfonyloxymethyl-1-propylspiro[decahydroquinolin-6,2'-(1',3'dioxolane)](3.7 mmole) produced in Step A in 10 ml of DMF was slowly added. Themixture was allowed to come to room temperature and was stirredovernight. The mixture was then poured into water. The product wasextracted into CHCl₃ /i-PrOH (3:1), which was then dried using sodiumsulfate and evaporated to give 960 mg ofrac-(3α,4aα,8aβ)-3-methylthiomethyl-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]as a brown oil.

Mass Spectrum: 299, 284, 270, 252, 198, 101.

C. Hydrolysis ofrac-(3α,4aα,8aβ)-3-methythiomethyl-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)

A solution of 1.35 g of rac-(3α,4aα,8aβ)-3-methylthiomethyl-1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane) in 50 ml of water and 20 ml of concentratedhydrochloric acid was prepared and stirred for 1 hour. It was thenpoured into ice. The resulting mixture was made basic. Then the productwas extracted into a solution of CHCl₃ /i-PrOH (3:1), which was driedusing sodium sulfate and evaporated to give 1.1 g of product. This waspassed through a silica gel column with hexane/THF (5:1) containing atrace of NH₄ OH. The fractions shown by TLC to contain rac-(3α,4aα,8aβ)-3-methylthiomethyl-1-propyldecahydroquinolin-6-one were combined. Yield900 mg.

EXAMPLE 28rac-(4aβ,7α,8aα)-7-Methylthiomethyl-1-propyl-4,4a,5,6,-7,8,8a,9-octahydro-2H-pyrazolo[3,4-g]quinoline

The title product was prepared using the process of Example 24 and theproduct of Preparation 16 as the starting material. The dihydrochloridesalt was then prepared and recrystallized from MeOH/EtOAC.

Mass Spectrum: 279, 264, 250, 232, 185, 170, 119, 87.

EXAMPLE 29rac-(5aβ,8α,9aα)-8-Methylthiomethyl-6-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrido-[2,3-g]quinazolin-2-amine

The title compound was prepared using the process of Example 25 and theproduct of Preparation 16 as the starting material.

Analysis, calculated: C, 62.71; H, 8.55; N, 18.28.

Found: C, 62.90; H, 8.73; N, 18.38.

Mass Spectrum: 306, 292, 277, 259, 245.

198, 184, 170, 146, 122.

Preparation 17 rac-(3α,4aα,8aβ)-Ethyl1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)-3-carboxylate

To a solution of 4.5g (14.5 mmole) of rac-(3β,4aα,8aβ)-ethyl1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)-3-carboxylate(Preparation 19) in 75 ml of THF at -78° C. was added 72.3 ml (72.3mmole) of a 1.0M solution of lithium diisopropylamide. The mixture wasstirred at 0° C. for 21/2 hours, then cooled to -78° C., and 20 ml ofacetic acid in 50 ml of THF at -78° C. was added. The mixture wasallowed to come to room temperature, and a gel formed. This was pouredinto water. The hydrogen ion concentration was adjusted to pH 11. Theproduct was extracted into CH₂ Cl₂, which was then dried using sodiumsulfate and evaporated to give 4.6 g of product. The isomers wereseparated on a silica gel column using hexane/EtOAC (3:1). The fractionsshown by TLC to contain the (3α,4aα,8aβ) racemate were combined to give2.0 g of an oil. The fractions shown by TLC to contain the (3α,4aα,8aβ)racemate were combined to give 1.0 g of product.

Preparation 18 rac-(3α,4aα, 8aβ)-Ethyl6-oxo-1-propyldecahydroquinoline-3-carboxylate

The title compound was prepared by acid hydrolysis of 2.0 g ofrac-(3α,4aα,8aβ)-ethyl 1-propyl-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)-3-carboxylate (Preparation 17) in 150 ml of watercontaining 30 ml of concentrated hydrochloric acid at room temperature.

EXAMPLE 30 rac-(4aβ,7α,8aα)-Ethyl2-amino-5-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo4,5-g]quinoline-7-carboxylate

The title compound was prepared using the general procedure of Example 3and the product of Preparation 18 as the starting material.

Mass Spectrum: m/e=323.

EXAMPLE 31rac-(4aβ,7α,8aα)-7-(2-Amino-5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo[4,5-g]quinoline)methanol

The title product was prepared by reducing 560 mg (1.8 mmole) ofrac-(4aβ,7α,8aα) -ethyl2-amino-5-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]-quinoline-7-carboxylate(Example 30) with 8.8 ml of a 1M solution of diisobutylaluminum hydride(8.8 mmole) in 100 ml of THF. Yield: 350 mg.

Mass Spectrum: m/e=281.

EXAMPLE 32rac-(4aβ,7α,8aα)-7-(5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo[4,5-g]quinoline)methanol

A solution of 360 mg (1.2 mmole) ofrac-(4aβ,-7α,8aα)-7-(2-amino-5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo4,5-g]quinoline)methanol(Example 31) in 30 ml of 85% phosphoric acid was cooled to 0°. Then 90mg (1.5 mmole) of sodium nitrite dissolved in as small an amount ofwater as possible was slowly added under the surface of the reactionmixture. The resulting mixture was added dropwise to 30 ml of 50%hypophosphorous acid (H₃ PO₂) at 0° C. The mixture was stirred at roomtemperature until gas evolution ceased. This took about 1 hour. Themixture was poured onto ice, and the hydrogen ion concentration of themixture was adjusted to pH 11. Water was added to dissolve theprecipitate that formed; then the product was extracted into a solutionof CHCl₃ /i-PrOH (3:1). This solution was dried using sodium sulfate andevaporated to give 280 mg of the title product. This was passed througha silica gel column with 5% MeOH/CH₂ Cl₂ containing a trace of NH₄ OH.The appropriate fractions were combined, and the dihydrobromide salt ofthe product was formed and recrystallized from MeOH/EtOAC.

Analysis, calculated: C, 39.27; H, 5.65; N, 6.54.

found: C, 39.01; H, 5.62; N, 6.78.

Preparations 19-24 and Examples 33-40 relate to the β racemates definedin formula (3) and to intermediates used in preparation thereof.

Preparation 19 rac-(3β,4aα,8aβ)-Ethyl1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate

A 5 g sample of ethyl 1'-propyl-trans-spiro-[1,3-dioxolane-2,6'-(1',2',4a',5',6',7',8',8a'-octahydroquinoline)]-3-carboxylate (Preparation 1) washydrogenated at room temperature in 200 ml of 2B ethanol using about 5 gof Raney® nickel with H₂ at 50 psi for 21/2 hours to give 4.49 g of thetitle product.

Preparation 20rac-(3β,4aα,8aβ)-3-(1-Propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanol

A solution of 2.6 g (67.5 mmole) of lithium aluminum hydride in 400 mlof THF was prepared. To this a solution of 17.5 g (56.3 mmole) ofrac-(3β,4aα,8aβ) -ethyl 1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate (Preparation 19) in 350 ml of THF wasslowly added. Then the following additions were made sequentially: 2.5ml of water, 2.5 ml of 15% NaOH, 7.5 ml of water. The mixture was thenfiltered through a pad of celite and the filtrate was evaporated,producing an oil. A glutanous precipitate formed. The oil was dissolvedin CH₂ Cl₂, which was then dried using sodium sulfate, filtered, andevaporated, giving 15.4 ofrac-(3β,4aα,8aβ)-3-(1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanol.

Preparation 21rac-(3β-4aα,8aβ)-3-Hydroxymethyl-1-propyldecahydroquinolin-6-one

The title product was prepared by hydrolyzing a 2.0 g sample ofrac-(3β,4aα,8aβ)-3-(1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)])methanol (Preparation 20) in a solution of 100 ml ofwater and 40 ml of concentrated HCl at room temperature.

EXAMPLE 33rac-(5aβ,8β,9aα)-8-(2-amino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazoline)methanol

The title compound was made using the procedure of Example 25 and theproduct of Preparation 21 as the starting material. The dihydrochloridesalt was then made and recrystalized from MeOH/EtOAC.

Mass Spectrum: 276, 247, 204, 168, 154, 146, 136, 126.

Analysis, calc: C, 51.58; H, 7.50; N, 16.04; 0, 20.30.

found: C, 51.81; H, 7.79; N, 15.91; 0, 20.17.

Preparation 22rac-(3β,4aα,8aβ)-3-Methoxymethyl-1-propyldecahydroquinolin-6-one

The title product was prepared using the procedures of Preparation 4 andthe product of Preparation 20 as the starting material.

EXAMPLE 34rac-(5aβ,8β,9aα)-8-Methoxymethyl-6-propyl-5,5a,6,7,8,-9,9a,10-octahydropyrido[2,3-g]quinazolin-2-amine

The title product was prepared using the procedure of Example 25 andrac-(3β,4aα,8aβ)-3-methoxy methyl-1-propyldecahydroquinolin.-6-one(Preparation 22) as the starting material.

Analysis calcd: C, 66.17; H, 9.02; N, 19.29.

found: C, 65.89; H, 8.89; N, 19.16.

Preparation 23rac-(3β,4aα,8aβ)-3-Methylthiomethyl-1-propyldecahydroquinolin-6-one

The title product was prepared fromrac-(3β,4aα,8aβ)-3-(1-propylspirodecahydroquinoline-6,2'-(1',3'-dioxolane)])methanol (Preparation 20) using the process ofPreparation 16. In Step B (substitution of methyl mercaptide formethylsulfonyloxy) it was necessary to heat the reaction to 70° C. fortwo hours after the mixture was stirred overnight at room temperature.

EXAMPLE 35rac-(5aβ,8β,9aα)-8-Methylthiomethyl-1-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolin-2-amine

The title compound was prepared from the product of Preparation 23 usingthe process of Example 25.

Mass spectrum: 306, 292, 277, 259, 245, 188, 146.

The monohydrochloride salt was formed and recrystallized fromMeOH/EtOAC.

M.P. >250° C.

Analysis Calcd: C, 56.04; H, 7.94; N, 16.34.

Found: C, 56.16; H, 7.73; N, 16.09.

Preparation 24 rac-(3β,4aα,8aβ)-Ethyl6-oxo-1-propyldecahydroquinoline-3-carboxylate

The title compound was prepared by hydrolyzing 1.0 g ofrac-(3β,4aα,8aβ)-ethyl1-propylspiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate(Preparation 19) in a solution of 100 ml of H₂ O and 20 ml ofconcentrated HCl at room temperature.

EXAMPLE 36 rac-(4aβ,7β,8aα)-Ethyl2-amino-5-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline-7-carboxylate

The title compound was prepared from rac-(3β,4aα,8aβ)-ethyl6-oxo-1-propyldecahydroquinoline-3-carboxylate (Preparation 24) usingthe general process as Example 3.

Mass spectrum: m/e=323.

EXAMPLE 37rac-(4aβ,7β,8aα)-7-(2-Amino-5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo[4,5-g]quinoline)methanol

The title compound was prepared by reducing 520 mg (1.6 mmole) ofrac-(4aβ,7β,8aαo) -ethyl2-amino-5-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline-7-carboxylate(Example 36) with 8.0 ml of 1M solution of diisobutylaluminum hydride(in CH₂ Cl₂) in 75 ml of THF.

Mass spectrum: m/e=281.

I.R.: 3297, 3103, 2918, 1760, 1541 cm⁻¹.

EXAMPLE 38rac-(4aβ,7β,8aα)-7-(5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo[4,5-g]quinoline)methanol

The title compound was prepared fromrac-(4aβ,7β,8aα)-7-(2-Amino-5-propyl-4,4a,5,6,7,8,8a-octahydrothiazolo[4,5-g]quinoline)methanol(Example 37) using the procedure of Example 32. The dihydrobromide saltwa formed and recrystallized from MeOH/EtOAC.

Mass spectrum: m/e=266.

I.R.: 3405, 1650 cm⁻¹.

Preparation 25 Ethyl8-[(phenylmethyl)amino]-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate

Ethyl 8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (352.8 g, 1.6 mole)was dissolved in ethyl alcohol (1500 ml), and benzylamine (365 g, 3.6mole) was added. The mixture was stirred, heated to about 50° C. forabout 2 hours, and then another equivalent of benzylamine (171 g, 1.6mole) was added. The mixture was then poured into water. The product wasextracted with methylene chloride, dried with sodium sulfate andevaporated to give an oil. Excess benzylamine was vacuum distilled offat 0.1 mm Hg and 60°-65° C. allowing the pot residue, which containedthe product, to reach 110° C. This was then diluted with methanol (1:1by volume). The resulting mixture was allowed to cool crystals formedand 395.4 g of white crystals were isolated by filtration.

A second crop of 75.6 g of tan crystals was isolated from the motherliquor, giving a total of 471.0 g of the title compound.

Preparation 26 Ethyl8-[(phenylmethyl)amino]-1,4-dioxaspiro[4.5]decane-7-carboxylate

Ethyl 8-(phenylmethyl)amino]-1,4-dioxaspiro-[4.5]-dec-7-ene-7-carboxylate (395.4 g, 1.3 mole) and acetic acid (75.0ml, 1.3 mole) were added to ethanol (4 1). Sodium cyanoborohydride (82.0g, 1. mole) was added in portions over 3 hours. The mixture was stirredovernight, then poured into water. The pH was adjusted to 10, and theproduct was extracted with methylene chloride, which was then dried withsodium sulfate and evaporated to give a yellow oil having small clearlumps in it. This was dissolved in THF and poured through 3 inches ofbasic alumina, which was then rinsed well with THF. The filtrate wasevaporated to give 397.2 g (99.9%) of the title product as ayellow-green oil.

Preparation 27 Ethyl 8-amino-1,4-dioxaspiro[4.5]decane-7-carboxylate

Ethyl 8-[(phenylmethyl)amino]-1,4-dioxaspiro -[4.5]-decane-7-carboxylate(397.2 g, 1.3 mole) was combined with 2563 ml of ethanol and 80 g of 5%palladium on activated carbon and hydrogenated at 50 p.s.i. for 6 hoursat 45°-50° C. The catalyst was separated by filtration, and the filtratewas evaporated. When taken up in methylene chloride a semi-solidprecipitated and was filtered out. The filtrate was evaporated to yield277.7 g (97.4%) of the title product.

Preparation 28 Ethyl8-amino-trans-1,4-dioxaspiro[4.5]decane-7-carboxylate

Sodium metal (27.7 g, 1.2 mole) was reacted with ethanol (1 1), thenethyl-8-amino-1,4-dioxaspiro-[4.5]-decane-7-carboxylate (137.7 g, 0.6mole) in ethanol (400 ml) was added. The mixture was refluxed for 11/2hours, then cooled to room temperature, poured into ice, and made basic.The product was extracted with methylene chloride, dried with sodiumsulfate and evaporated to give 118.0 g (85.7%) of the title product.

Preparation 29 Ethyl8-(propylamino)-trans-1,4-dioxaspiro[4.5]decane-7-carboxylate

Ethyl 8-amino-trans-1,4-dioxaspiro4.5]decane -7-carboxylate (118.0 g,0.52 mole) was dissolved in DMF (1 1) and potassium carbonate (107 g,0.77 mole) and propyl bromide (158.4 g, 1.3 mole) were added. Themixture was heated to 50° C. for three hours, then poured into water,and the hydrogen ion concentration was adjusted to pH 10. The productwas extracted with methylene chloride, dried and evaporated to give 136g of a dark orange oil.

Preparation 30 Ethyl8-[(3-ethoxy-3-oxopropyl)propylamino]-trans-1,4-dioxaspiro[4.5]decane-7-carboxylate

Ethyl 8-(propylamino)-trans-1,4-dioxaspiro -[4.5]-decane-7-carboxylate(129.6 g, 0.48 mole) was dissolved in ethanol (1500 ml), then ethylacrylate (479 g, 4.8 mole) was added. The mixture was refluxedovernight, then additional ethyl acrylate (479 g, 4.8 mole) was added.The mixture was refluxed for 24 hours, at which time a third addition ofethyl acrylate (479 g, 0.48 mole) was made, followed by 60 hours ofreflux. The mixture was then cooled to room temperature, poured intowater, and the hydrogen ion concentration was adjusted to pH 10. Theproduct was extracted with methylene chloride, dried with sodium sulfateand evaporated to give 177.4 g of crude product. This was purified byHPLC to give 102.1 g of the title product (59.8%).

EXAMPLE 39 Ethyl 4-oxo-1-propyl-trans-spiro[decahydroquinoline-6,2'-(1',3'-dioxolane)]-3-carboxylate

THF (500 ml) was added to potassium t-butoxide (61.6 g, 0.55 mole), andto this mixture ethyl8-[(3-ethoxy-3-oxapropyl)propylamino]-1,4-dioxaspiro-[4.5]-decane-7-carboxylate(98.0 g, 0.27 mole) dissolved in 500 ml of THF was slowly added. Themixture was then poured onto ice and the hydrogen ion concentration wasadjusted to pH 10. The product was extracted with methylene chloride,dried with sodium sulfate, and evaporated to yield 87.2 g (97.7%) of thetitle product.

The compounds of this invention are useful as prolactin inhibitors andas such they can be employed in the treatment of inappropriate lactationsuch as postpartum lactation and galactorrhea. As evidence of theirutility in the treatment of conditions in which it is desirable toreduce the prolactin level, the compounds of this invention have beenshown to inhibit prolactin according to the following procedure.

Adult male rats of the Sprague-Dawley strain weighing about 200 g werehoused in an air-conditioned room with controlled lighting (lights on 6a.m.-8 p.m.) and fed lab chow and water ad libitum. In the testing ofthe reserpinized male rat at 50 μg/kg of compound under test, each ratreceived an intraperitoneal injection of 2.0 mg. of reserpine in aqueoussuspension 18 hours before administration of the test drug. The purposeof the reserpine was to keep prolactin levels uniformly elevated. In thetesting of the nonreserpinized male rat at 1000 μg/Kg of compound undertest, the preceding procedure was omitted. The compounds under test weredissolved in 10 percent ethanol, and were injected intraperitoneally.Each compound was administered at each dose level to a group of 10 rats,and a control group of 10 intact males received an equivalent amount of10 percent ethanol. One hour after treatment, all rats were killed bydecapitation, and 150 μl aliquots of serum were assayed for prolactin.

The difference between the prolactin level of the treated rats andprolactin level of the control rats, divided by the prolactin level ofthe control rats gives a number that, when multiplied by 100, is thepercent inhibition of prolactin secretion attributable to the compoundsof this invention. These inhibition percentages are given in Table 1.

Dopamine agonists have been found to affect turning behavior in6-hydroxydopamine-lesioned rats in a test procedure designed to uncovercompounds useful for the treatment of Parkinsonism. In this test,nigro-neostriatal-lesioned rats are employed, as prepared by theprocedure of Ungerstedt and Arbuthnott, Brain Res, 24, 485 (1970). Acompound having dopamine agonist activity and the ability to passthrough the blood brain barrier into the striatum of the brain causesthe rats to turn in circles contralateral to the side of the lesion.After a latency period, which varies from compound to compound, thenumber of turns is counted over a 15-minute period.

Results obtained from such testing are set forth for representativecompounds in Table 1. In the table, column 1 identifies the compound byexample number; columns 2 and 3, the percent prolactin inhibition at 50μg/Kg for reserpinized male rats and 1000 μg/Kg for nonreserpinized malerats; and column 4, the percent of test animals exhibiting turningbehavior.

                  TABLE 1                                                         ______________________________________                                                Percent Prolactin                                                                              % of Rats Exhibiting                                 Compound                                                                              Inhibition       Turning Behavior                                     (Ex. No.)                                                                             50 μg/Kg.sup.a                                                                       1000 μg/Kg.sup.b                                                                      1.0 mg/Kg                                        ______________________________________                                         1      71        --          0                                                2      76        --         82                                                6      --        90         --                                                8      --        84         80                                               11      --        84         33                                               13      14        94          0                                               14      62        --          0                                               15      83        --         100                                              16      27        --         --                                               22      88        --         --                                               23(1H)  --        83         --                                               23(2H)  --        84         --                                               24       3        70         --                                               25      --        87         --                                               26      --        89         --                                               27      --        89         --                                               28      --        85         --                                               34      --        92         --                                               35      --        95         --                                               ______________________________________                                         .sup.a Percent reduction from controls in serum prolactin levels followin     a dose of 50 μg/Kg in the reserpinized male rat.                           .sup.b Percent reduction from controls in serum prolactin levels followin     a dose of 1000 μg/Kg in the nonreserpinized male rat.                 

Dopamine agonists which pass through the blood-brain barrier and enterthe brain have been shown to decrease brain levels of dopaminemetabolites such as 3,4-dihydroxy phenylacetic acid (DOPAC) andhomovanillic acid (HVA). Tests described by Perry and Fuller, Soc.Neurosci. Abstr., 5, 348 (1979) evaluate the effect compounds have ondopamine metabolite levels in the brain. Compounds of this inventionwere subjected to these testing procedures and the results ofrepresentative compounds are given in Table 2.

Dopamine agonists that enter the brain give rise to elevated serumcorticosterone levels. Compounds of this invention were subjected to thetesting procedure of Solem and Brink-Johnsen, Scand. J. Clin. Lab.Invest. (Suppl. 80) 17:1 (1965) to determine their effects on serumcorticosterone levels. Results of representative compounds are given inTable 2 below. In the table, column 1 identifies the compound by examplenumber; column 2 and 3, minimum effective dose to alter brain dopaminemetabolite levels; and column 4, minimum effective dose causing serumcorticosterone elevation.

                  TABLE 2                                                         ______________________________________                                        Minimum Effective Dose, μg/Kg, i.p.                                                                   Serum                                              Compound                                                                              Brain Dopamine Metabolites                                                                       Corticosterone                                     (Ex. No.)                                                                             DOPAC.sup.a  HVA.sup.b Elevation                                      ______________________________________                                         1      >3000        1000      >3000                                           2      300          300       300                                             6       30           30        30                                             8      100          100       100                                            14      >3000        >3000     >3000                                          22      100           30       1000                                           25      300          300       1000                                           26      >3000         30        30                                            27       30           30        30                                            28      1000         100       100                                            35       10           10       100                                            ______________________________________                                         .sup.a DOPAC = 3,4dihydroxyphenylacetic acid                                  .sup.b HVA = homovanillic acid                                           

Compounds of Examples 1 and 14 are peripherally selective dopamineagonists. They are active in the inhibition of serum prolactin secretionby activation of dopamine receptors on the pituitary, a tissue which isnot protected by the blood-brain barrier. These compounds do not elicitturning in the 6-hydroxydopamine-lesioned rat or cause changes in thelevels of dopamine metabolites or serum corticosterone, which areactivities mediated in brain regions protected by the blood-brainbarrier. These compounds would have utility to inhibit prolactinsecretion without causing central dopaminergic side effects.

The compounds of this invention reduce the blood pressure ofspontaneously hypertensive rats, as shown by the following experiment:

Adult male spontaneously hypertensive rats (SHR) (Taconic Farms,Germantown, N.Y.) weighing approximately 300 g were anesthetized withpentobarbital sodium (60 mg/kg, i.p.). The trachea was cannulated andthe SHR respired room air. Pulsatile arterial blood pressure wasmeasured from a cannulated carotid artery using a Statham transducer(P23 ID). Mean arterial blood pressure was calculated as diastolic bloodpressure plus 1/3 pulse pressure. Drug solutions were administered i.v.through a catheter placed in a femoral vein. Arterial blood pressure wasrecorded on a multichannel oscillograph (Beckman, Model R511A). Fifteenminutes were allowed to elapse following surgery for equilibration ofthe preparation.

Table 3, which follows, gives the results of this test forrepresentative compounds of this invention. In Table 3, column 1identifies the compound by example number; and columns 2, 3, 4, 5, 6 and7, the percent change in blood pressure at 0.1 μg/kg, 1 μg/kg, 10 μg/kg,100 μg/kg, 1000 μg/kg and 10,000 μg/kg, respectively.

                                      TABLE 3                                     __________________________________________________________________________          % Change in Mean Arterial Blood Pressure in                             Compound                                                                            Anesthetized Spontaneously Hypertensive Rats                            (Ex. No.)                                                                           0.1 μg/kg                                                                         1 μg/kg                                                                           10 μg/kg                                                                          100 μg/kg                                                                         1000 μg/kg                                                                        10000 μg/kg                       __________________________________________________________________________     5    -5.7 ± 0.3                                                                        -24.2 ± 1.6                                                                       -36.8 ± 6.2                                                                       -43.0 ± 3.7                                                                       -48.3 ± 2.8                                                                       --                                    6    -1.4 ± 3.6                                                                        -15.2 ± 3.7                                                                       -35.6 ± 5.2                                                                         8.0 ± 2.7                                                                       --     --                                    8    --     -18.0 ± 2.2                                                                       -25.3 ± 2.2                                                                       -30.6 ± 1.7                                                                       -17.2 ± 3.5                                                                       --                                   11    --     -11.0 ± 4.0                                                                       -18.0 ± 6.6                                                                       -26.7 ± 7.2                                                                        -4.3 ± 4.2                                                                       --                                   12    --      +2.8 ± 0.8                                                                        +3.2 ± 0.6                                                                        -1.6 ± 3.1                                                                        -8.9 ± 1.5                                                                       -37.8 ± 2.1                       13    --      - 8.6 ± 0.8                                                                       -8.4 ± 1.1                                                                       -14.9 ± 0.7                                                                       -14.6 ± 2.8                                                                       --                                   16    --      +3.6 ± 0.3                                                                        +3.2 ± 0.6                                                                       -10.9 ± 1.1                                                                       -28.6 ± 3.8                                                                       --                                   19    --      +4.0 ± 1.5                                                                        +1.5 ± 1.0                                                                        -8.8 ± 1.4                                                                       -13.3 ± 1.0                                                                       --                                   22    -5.8 ± 1.4                                                                        -19.0 ± 1.3                                                                       -20.0 ± 1.6                                                                       -44.2 ± 2.0                                                                       -48.6 ± 0.8                                                                       --                                   24    --      -4.2 ± 1.6                                                                        -8.4 ± 0.6                                                                       -18.4 ± 2.8                                                                       -18.1 ± 0.9                                                                       --                                   26    --     -10.8 ± 2.0                                                                       -19.4 ± 1.6                                                                       -27.6 ± 2.0                                                                       -44.1 ± 3.4                                                                       --                                   32    --      -8.4 ± 1.2                                                                       -18.1 ± 1.0                                                                       -37.1 ± 1.0                                                                       -40.4 ± 3.9                                                                       --                                   34    --     -20.2 ± 2.1                                                                       -39.2 ± 3.5                                                                       -27.2 ± 5.4                                                                       -13.5 ± 2.3                                                                       --                                   35    -18.9 ± 1.8                                                                       -25.1 ± 2.2                                                                       -33.6 ± 2.4                                                                       -12.2 ± 1.5                                                                       --     --                                   38    +5.2 ± 2.2                                                                         -9.8 ± 2.0                                                                       -20.6 ± 2.2                                                                       -27.1 ± 6.2                                                                       -37.0 ± 1.3                                                                       --                                   __________________________________________________________________________

The compounds of this invention are administered for therapeuticpurposes in a variety of formulations as illustrated below.

Hard gelatin capsules are prepared using the following ingredients:

    ______________________________________                                                     Quantity (mg./capsule)                                           ______________________________________                                        Active compound                                                                              .1-2 mg                                                        Starch dried   200                                                            Magnesium stearate                                                                            10                                                            ______________________________________                                    

The above ingredients are mixed and filled into hard gelatin capsules.

A tablet formulation is prepared using the ingredients below:

    ______________________________________                                                       Quantity (mg./tablet)                                          ______________________________________                                        Active compound  .1-2 mg                                                      Cellulose, microcrystalline                                                                    400                                                          Silicon dioxide, fumed                                                                          10                                                          Stearic acid      5                                                           ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 1-2 mg. of active ingredient aremade up as follows:

    ______________________________________                                        Active ingredient       .1-2   mg.                                            Starch                  45     mg.                                            Microcrystalline cellulose                                                                            35     mg.                                            Polyvinylpyrrolidone    4      mg.                                            (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                           4.5    mg.                                            Magnesium stearate      0.5    mg.                                            Talc                    1      mg.                                            ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Capsules each containing 0.1-2 mg. of medicament are made as follows:

    ______________________________________                                        Active ingredient      .1-2   mg.                                             Starch                 59     mg.                                             Microcrystalline cellulose                                                                           59     mg.                                             Magnesium stearate     2      mg.                                             ______________________________________                                    

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules.

Suspensions each containing 0.1-2 mg. of medicament per 5 ml. dose aremade as follows:

    ______________________________________                                        Active ingredient       .1-2   mg.                                            Sodium carboxymethyl cellulose                                                                        50     mg.                                            Syrup                   1.25   ml.                                            Benzoic acid solution   0.10   ml.                                            Flavor                  q.v.                                                  Color                   q.v.                                                  Purified water to       5      ml.                                            ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethylcellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

For oral administration, tablets, capsules or suspensions containingfrom about 0.1 to about 2 mg. of active drug per dose are given 3-4times a day, giving a daily dosage of 0.3 to 8 mgs. or, for a 75 kgperson, about 4.0 to about 107 mcg/kg. The intravenous dose is in therange from about 0.1 to about 100 mcg./kg.

We claim:
 1. A BCD tricyclic ergoline part-structure analogue of theformula (1) ##STR34## wherein: the C and D rings are trans fused;R¹ is(C₁ -C₃) alkyl, allyl, or cyclopropylmethyl; R² is hydrogen, CH₂ OH, CH₂OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂ R⁶ or CONR⁷ R⁸, where R⁶ ishydrogen, (C₁ -C₄) alkyl or benzyl, and R⁷ and R⁸ are independentlyselected from hydrogen (C₁ -C₄) alkyl, phenyl, benzyl, and phenethyl; R³is hydrogen, OH, NH₂, NHCOR⁹ or NHSO₂ NR⁹ R¹⁰, where R⁹ and R¹⁰ areindependently selected from hydrogen, (C₁ -C₄) alkyl, and phenyl, or R³and R⁵ combine to form ═O or ═NOH; R⁴ and R⁵ are both hydrogen, orcombine to form a carbon-carbon bond, except that R⁴ is hydrogen when R⁵combines with R³ to form ═O or ═NOH; provided that one of R² and R³ ishydrogen and the other is not hydrogen, and further provided that R² ishydrogen unless R⁴ and R⁵ combine to form a carbon-carbon bond; and##STR35## where R¹¹ and R¹² are independently hydrogen or (C₁ -C₃)alkyl, or a pharmaceutically acceptable salt thereof.
 2. A compound ofclaim 1 wherein R⁴ and R⁵ combine to form a carbon-carbon bond.
 3. Acompound of claim 2 wherein R¹ is n-propyl.
 4. A compound of claim 1wherein R³ is OH, NH₂, NHCOR⁹ or NHSO₂ NR⁹ R¹⁰, where R⁹ and R¹⁰ are asdefined in claim
 1. 5. A compound of claim 4 wherein R¹ is n-propyl. 6.A compound of claim 4 as a racemate wherein the relative stereochemistryof the enantiomers is (4aβ,8α,8aα) or (5aβ,9α,9aα).
 7. A compound ofclaim 4 as a racemate wherein the relative stereochemistry of theenantiomers is (4aβ,8β,8aα) or (5aβ,9β,9aα).
 8. A compound of claim 1wherein R³ and R⁵ combine to form oxo or hydroxyimino and R² and R⁴ arehydrogen.
 9. A compound of claim 1, wherein R² is CH₂ OH.
 10. A compoundof claim 1 wherein R² is CH₂ OCH₃.
 11. A compound of claim 1 wherein R²is CH₂ SCH₃.
 12. A compound of claim 1 wherein R² is CO₂ R⁶.
 13. Acompound of claim 1 wherein R³ is OH.
 14. A compound of claim 1 which israc-)4aβ,8β,8aα)-2-amino-6-propyl-5,5a,6,7,8,9,9a,10-octahydropyrido[2,3-g]quinazolin-9-olor a pharmaceutically acceptable salt thereof.
 15. A BCD tricyclicergoline part-structure analogue having the structure (2a) or (2b)##STR36## where R¹ is (C₁ -C₃) alkyl, allyl, or cyclopropylmethyl;R² isCH₂ OH CH₂ OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂ R⁶, or CONR⁷ R⁸,where R⁶ is hydrogen, (C₁ -C₄) alkyl or benzyl, and R⁷ and R⁸ areindependently selected from hydrogen, (C₁ -C₄) alkyl, phenyl benzyl, andphenethyl; and B is a pyridol[2,3-g]quinazoline derivative of theformula ##STR37## where R¹¹ and R¹² are each independently hydrogen or(C₁ -C₃) alkyl, or a pharmaceutically acceptable salt thereof.
 16. Acompound of claim 15 wherein R¹ is n-propyl.
 17. A compound of claim 15wherein R² is CH₂ OH.
 18. A compound of claim 15 wherein R² is CH₂ OCH₃.19. A compound of claim 15 wherein R² is CH₂ SCH₃.
 20. A compound ofclaim 15 wherein R² is CO₂ R⁶.
 21. A BCD tricyclic ergolinepart-structure analogue having the structure (3a) or (3b) ##STR38##wherein R¹ is (C₁ -C₃) alkyl, allyl, or cyclopropylmethyl; andR² is CH₂OH, CH₂ OCH₃, CH₂ SCH₃, CH₂ SOCH₃, CH₂ SO₂ CH₃, CO₂ R⁶, or CONR⁷ R⁸,where R⁶ is hydrogen, (C₁ -C₄) alkyl or benzyl, and R⁷ and R⁸ areindependenly selected from hydrogen, (C₁ -C₄) alkyl, phenyl, benzyl, andphenethyl; and ##STR39## wherein R¹¹ and R¹² are independently hydrogenor (C₁ -C₃) alkyl, or a pharmaceutically acceptable salt thereof.
 22. Acompound of claim 21 wherein R¹ is n-propyl.
 23. A compound of claim 21wherein R² is CH₂ OH.
 24. A compound of claim 21 wherein R² is CH₂ OCH₃.25. A compound of claim 21 wherein R² is CH₂ SCH₃.
 26. A compound ofclaim 21 wherein R² is CH₂ SOCH₃.
 27. A compound of claim 21 wherein R²is CO₂ R⁶.
 28. A pharmaceutical formulation comprising a compound ofclaim 15 associated with a pharmaceutically acceptable carrier ordiluent therefor.
 29. A pharmaceutical formulation comprising a compoundof claim 15 associated with a pharmaceutically acceptable carrier ordiluent therefor.
 30. A pharmaceutical formulation comprising a compoundof claim 21 associated with a pharmaceutically acceptable carrier ordiluent therefor.